Substituted cycloalkene derivative

ABSTRACT

A compound of formula (I) 
                         
Wherein X, Y, ring A, ring B, l, m, R 1 , R 2 , R 4  and R 5  are as defined herein, to supress intracellular signal transduction or cell activation induced by endotoxin and to suppress cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts therefor, a preparation method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient which is superior in prophylaxis and/or treatment of diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), that are associated with intracellular signal transduction or cell activation induced by endotoxin and to cell responses to the intracellular signal transduction and cell activation.

CROSS-REFERENCE TO RELATED APPLICATION

This Application is a Section 371 National Stage Application of International Application No. PCT/JP2006/318103, filed 13 Sep. 2006 and published as WO 2007/032362 A1 on 22 Mar. 2007, which claims the priority from the Japanese application 2005-267504, filed 14 Sep. 2005, the subject matter of which are hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to a novel compound which has an action to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction or cell activation being induced by endotoxin, and to suppress the generation of inflammatory mediators such as TNF-α due to the intracellular signal transduction and cell activation, and which is useful as a prophylactic and/or therapeutic agent for various diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), a production method therefor and a use thereof.

BACKGROUND ART

Sepsis is a systemic inflammatory response syndrome (SIRS) which occurs due to an excess inflammatory response of a biological body against bacterial infection, and is a disease which may result in death when it is accompanied by shock or organ failure. Since there are only a few agents that are effective against sepsis until now, it is considered to be a disease that is difficult to prevent and treat. However, since its fatality is high and the number of patients is large, development of therapeutic agents for it is particularly important (for example, refer to Non-patent document 1).

Endotoxin (lipopolysaccharide, LPS), which is a membrane component of bacteria, acts against cells such as monocytes, macrophages and vascular endothelial cells, induces an excess generation of various inflammatory mediators such as TNF-α and the like, causes sudden blood pressure reduction, blood coagulation disorders, cardiovascular disturbances and the like in addition to systemic inflammatory responses, and thus exhibits sepsis (for example, refer to Non-patent document 2). Lipid A, which corresponds to lipopolysaccharide and its partial structure, activates intracellular signal transduction via TLR4 (Toll-like receptor 4), which is a functional cell surface receptor, after binding with CD14 (for example, refer to Non-patent document 3). Accordingly, lipid A initiates various cell responses represented by the generation of inflammatory mediators. Therefore, it is considered that a substance which suppresses the intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-α, can be an effective prophylactic and therapeutic agent for sepsis (for example, refer to Non-patent document 3, Non-patent document 4, Patent document 1 and Patent document 2).

Intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-α, lead to development and progress of various diseases such as ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis and leukemia, in addition to the aforementioned sepsis (for example, Non-patent document 5 and Patent document 3).

Therefore, a substance which suppresses intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, is considered to be effective as a prophylactic and/or therapeutic agent for these various diseases, and thus the development of an excellent therapeutic agent has been desired.

-   [Non-patent Document 1] Iqbal et al., Expert Opin. Emerging Drugs,     Vol. 7, page 111, 2002 -   [Non-patent Document 2] Hawkins et al., Current Topics in Medicinal     Chemistry, Vol. 4, page 1147, 2004 -   [Non-patent Document 3] Beutler, Nature, Vol. 430, pages 257-263,     2004 -   [Non-patent Document 4] Kakutani et al., Inflammation Research, Vol.     48, page 461, 1999 -   [Non-patent Document 5] Donald N. Cook et al., Nature Immunology,     Vol. 5, pages 975-979, 2004 -   [Patent Document 1] Japanese Patent Application (Kokai) No.     2000-178246 -   [Patent Document 2] Japanese Patent Application (Kokai) No.     2004-2370 -   [Patent Document 3] International Publication WO 00/41698 Pamphlet

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

As a result of conducting extensive studies on the pharmacological activity of various substituted cycloalkene derivatives for the purpose of developing a compound which has an activity to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction or the cell activation being induced by endotoxin, and to suppress various cell responses induced by the intracellular signal transduction and cell activation, such as an excess generation of inflammatory mediators such as TNF-α, the inventors of the present invention found that a substituted cycloalkene derivative having a unique structure possesses an excellent suppressing effect against intracellular signal transduction or cell activation induced by endotoxin, and against cell responses induced by the intracellular signal transduction and cell activation, such as an excess generation of inflammatory mediators such as TNF-α, and found that it is useful as a prophylactic and/or therapeutic agent for various diseases such as sepsis which are associated with intracellular signal transduction or cell activation induced by endotoxin, and with cell responses induced by the intracellular signal transduction and the cell activation, thereby leading to completion of the present invention.

The present invention provides a substituted cycloalkene derivative which possesses an activity to suppress intracellular signal transduction or cell activation induced by endotoxin, and cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts thereof, a production method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient, which is excellent for prophylaxis and/or treatment of various diseases caused by intracellular signal transduction or cell activation induced by endotoxin, and caused by cell responses including an excess generation of inflammatory mediators such as TNF-α, the cell responses being induced by the intracellular signal transduction and cell activation.

Means for Solving the Problems

Accordingly, the present invention provides:

(1) A compound represented by the general formula (I):

{wherein

X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, X and Y together represent a substituent of ring B, or X and Y each represents a hydrogen atom.

-   1) In the case where X and Y represent a group in which X and Y     together with the carbon atom of ring B to which they are bound form     ring A: -   ring A represents

a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkanoyl group which may be substituted with a group selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂,

-   the heterocyclyl ring may include an unsaturated bond, may form a     fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring     or 3- to 7-membered cycloalkyl ring, and ring A, including the fused     ring or spiro ring, may be substituted with the same or different 1     to 4 groups selected from the group consisting of an oxo group, a     thioxo group, Substituent group α, a cyclopropyl a C₁-C₆ alkyl     group, -   a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups     selected from Substituent group α, -   a C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups     selected from Substituent group α, and a C₂-C₆ alkynyl group which     may be substituted with 1 to 5 groups selected from Substituent     group α]     or -   a 3- to 7-membered cycloalkyl ring (the cycloalkyl ring may include     an unsaturated bond, -   may form a fused ring or spiro ring with a 3- to 7-membered     heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and ring A,     including the fused ring or spiro ring, may be substituted with the     same or different 1 to 4 groups selected from the group consisting     of Substituent group α, a cyclopropyl C₁-C₆ alkyl group, -   a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups     selected from Substituent group α, -   a C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups     selected from Substituent group α, and -   a C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups     selected from Substituent group α). -   2) In the case where X and Y together represent a substituent of     ring B: -   X and Y represent an oxo group or a thioxo group. -   l and m, independently from each other, represent an integer of 0 to     3, and -   l+m is 1 to 3. -   R¹ represents -   an aliphatic hydrocarbon group which may be substituted with a group     selected from Substituent group β and Substituent group γ (the     aliphatic hydrocarbon group represents a C₁-C₂₀ alkyl group, C₃-C₁₀     cycloalkyl group, C₄-C₁₂ cycloalkylalkyl group, C₃-C₆ alkenyl group     or C₃-C₆ alkynyl group), -   a phenyl group which may be substituted with a group selected from     Substituent group δ, -   a group having the formula OR⁴ (R⁴ represents a hydrogen atom or an     aliphatic hydrocarbon group which may be substituted with a group     selected from Substituent group β and Substituent group γ, the     aliphatic hydrocarbon group represents the same as aforementioned)     or -   a halogen atom. -   n represents an integer of 0 to 3. -   R² represents a hydrogen atom, -   a C₁-C₆ alkyl group which may be substituted with a group selected     from Substituent group β, -   a C₂-C₆ alkenyl group which may be substituted with a group selected     from Substituent group β, or -   a C₂-C₆ alkynyl group which may be substituted with a group selected     from Substituent group β. -   R³ represents -   a phenyl group which may be substituted with a group selected from     Substituent group ε, or -   a 5- or 6-membered heteroaryl group which may be substituted with a     group selected from Substituent group ε (the heteroaryl group     includes 1 to 3 hetero atoms selected from a nitrogen atom, oxygen     atom and sulfur atom). -   R⁵ represents a hydrogen atom, -   a C₁-C₆ alkyl group which may be substituted with a group selected     from Substituent group β, -   a C₂-C₆ alkenyl group which may be substituted with a group selected     from Substituent group β, or -   a C₂-C₆ alkynyl group which may be substituted with a group selected     from Substituent group β. -   Provided that in the case where R³ is a phenyl group which may be     substituted with a group selected from Substituent group ε, X and Y     represent the aforementioned (1) or (2). -   Substituent group α represents -   a hydroxy group, halogen atom, C₁-C₆ alkoxy group, halogeno C₁-C₆     alkoxy group, carboxy group, C₁-C₆ alkoxy-carbonyl group; -   carbamoyl group which may be substituted with a group selected from     a C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆     alkanoyl group or C₂-C₆ alkenyl-carbonyl group; and a group having     the formula NR⁶R⁷. -   R⁶ and R⁷, independently from each other, represent a hydrogen atom,     C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆     alkanoyl group or C₂-C₆ alkenyl-carbonyl group, or together with the     nitrogen atom to which they are bound form a heterocyclyl group. -   Substituent group β represents -   an oxo group, hydroxy group, cyclopropyl group, C₁-C₆ alkoxy group,     C₁-C₆ alkylthio group, nitro group, halogen atom, cyano group,     carboxy group, C₁-C₁₀ alkoxy-carbonyl group, C₁-C₆ alkanoyl group,     C₂-C₄ alkenyl-carbonyl group, C₂-C₆ alkanoyloxy group, C₂-C₄     alkenyl-carbonyloxy group; -   carbamoyl group which may be substituted with a group selected from     a C₁-C₄ alkyl group, phenyl group, C₁-C₇ acyl group and C₁-C₄     alkoxy-phenyl group; -   thiocarbamoyl group which may be substituted with a C₁-C₄ alkyl     group or phenyl group; -   carbamoyloxy group which may be substituted with a C₁-C₄ alkyl group     or phenyl group; -   C₁-C₆ alkanoylamino group, C₁-C₁₀ alkoxy-carboxamide group, C₁-C₁₀     alkoxy-carbonyloxy group, and -   ureido group which may be substituted with a C₁-C₄ alkyl group or     phenyl group. -   Substituent group γ represents -   a heterocyclic group, C₃-C₁₀ cycloalkyloxy group, C₆-C₁₀ aryloxy     group, C₇-C₁₉ aralkyloxy group, heterocyclyloxy group, C₃-C₁₀     cycloalkylthio group, C₆-C₁₀ arylthio group, C₇-C₁₉ aralkylthio     group, heterocyclylthio group, heterocyclylsulfinyl group,     heterocyclylsulfonyl group, C₃-C₆ cycloalkyloxy-carbonyl group,     C₆-C₁₀ aryloxy-carbonyl group, C₇-C₁₉ aralkyloxy-carbonyl group,     heterocyclyloxycarbonyl group, C₆-C₁₀ aryl-carbonyl group, C₉-C₁₀     aryl-carbonyloxy group, C₆-C₁₀ aryl-carbonylamino group, C₆-C₁₀     aryloxy-carboxamide group, C₇-C₁₉ aralkyloxy-carboxamide group,     C₆-C₁₀ aryloxy-carbonyloxy group, C₇-C₁₉ aralkyloxy-carbonyloxy     group, C₃-C₁₀ cycloalkyloxy-carbonyloxy group and C₆-C₁₀ aryl group     which may be substituted with a group selected from Substituent     group β. -   Substituent group δ represents -   a hydroxy group, nitro group, cyano group, halogen atom, C₁-C₆ alkyl     group, halogeno C₁-C₆ alkyl group, C₁-C₆ alkoxy group, halogeno     C₁-C₆ alkoxy group, carboxy group, C₁-C₆ alkanoyl group, C₁-C₆     alkoxy-carbonyl group, C₁-C₆ alkanoylamino group, C₁-C₆ alkylthio     group, carbamoyl group, C₁-C₆alkyl-carbamoyl group, C₁-C₆     alkoxy-carbonyl C₁-C₆ alkyl-carbamoyl group, 1,3-diacylguanidino     C₁-C₆ alkyl group, a group having the formula NR⁶R⁷ (R⁶ and R⁷ are     the same as R⁶ and R⁷ of Substituent group α), C₃-C₆ cycloalkyl     group, C₆-C₁₀ aryl group and 5-membered heteroaryl group. -   Substituent group ε represents -   a hydroxy group, nitro group, cyano group, halogen atom, C₁-C₁₄     alkyl group, cyclopropyl C₁-C₁₄ alkyl group, halogeno C₁-C₁₄ alkyl     group, C₁-C₁₄ alkoxy group, halogeno C₁-C₁₄ alkoxy group, carboxy     group, C₁-C₁₄ alkanoyl group, C₁-C₁₄ alkoxy-carbonyl group, C₁-C₁₄     alkanoylamino group, C₁-C₁₄ alkylthio group, carbamoyl group, C₁-C₁₄     alkyl-carbamoyl group, C₁-C₁₄ alkoxy-carbonyl C₁-C₁₄ alkyl-carbamoyl     group, 1,3-diacylguanidino C₁-C₁₄ alkyl group, a group having the     formula NR⁶R⁷ (R⁶ and R⁷ are the same as R⁶ and R⁷ of Substituent     group α), C₃-C₆ cycloalkyl group, C₆-C₁₀ aryl group and 5-membered     heteroaryl group} -   or a pharmacologically acceptable salt thereof,

(2) The compound or pharmacologically acceptable salt thereof according to the aforementioned (1), wherein l is 0 and m is an integer of 1 to 3,

(3) The compound or pharmacologically acceptable salt thereof according to the aforementioned (1), wherein l is 0 and m is 2,

(4) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein

-   X and Y together with the carbon atom of ring B form ring A, and     ring A is -   a 3- to 7-membered heterocyclyl ring -   [in the heterocyclyl ring, X and Y, independently from each other,     represent any one selected from a carbon atom, a group having the     formula NR (R represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆     alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkanoyl group which may be     substituted with a group selected from Substituent group α), an     oxygen atom, a sulfur atom, a group having the formula SO and a     group having the formula SO₂,

the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered cycloalkyl ring, and

ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆ alkyl group and a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α]

or

-   a 3- to 7-membered saturated cycloalkyl ring -   (the 3- to 7-membered saturated cycloalkyl ring may be substituted     with 1 or 2 groups selected from the group consisting of a hydroxy     group, hydroxymethyl group, 1,2-dihydroxyethyl group,     1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and     acetylamino group),

(5) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein

-   X and Y represent a group in which X and Y together with the carbon     atom of ring B form ring A, and ring A is -   a 3- to 7-membered heterocyclyl ring -   [in the heterocyclyl ring, X and Y, independently from each other,     represent any one selected from a carbon atom, an oxygen atom, a     sulfur atom, a group having the formula SO and a group having the     formula SO₂, -   the heterocyclyl ring may form a fused ring or spiro ring with a 5-     or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or     2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered     cycloalkyl ring, and -   ring A, including the fused ring or spiro ring, may be substituted     with the same or different 1 to 4 groups selected from the group     consisting of an oxo group, a thioxo group, Substituent group α and     a C₁-C₆ alkyl group which may be substituted with 1 to 4 groups     selected from Substituent group α]     or -   a 3- to 5-membered saturated cycloalkyl ring -   (the 3- to 5-membered saturated cycloalkyl ring may be substituted     with 1 or 2 groups selected from the group consisting of a     hydroxymethyl group, 1,2-dihydroxyethyl group,     1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and     acetylamino group),

(6) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein

-   X and Y represent a group in which X and Y together with the carbon     atom of ring B form ring A, and ring A is -   a 3- to 7-membered heterocyclyl ring -   [the 3- to 7-membered heterocyclyl ring is -   oxirane, oxolane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane,     1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane,     1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or     1,3-oxathiepane,

these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and

ring A, including the fused ring or spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α (Substituent group α represents a hydroxy group and a group having the formula NR⁶R⁷, and R⁶ and R⁷, independently from each other, represent a hydrogen atom or C₁-C₆ alkanoyl group), a methyl group, an ethyl group and a C₁-C₆ alkyl group which is substituted with 1 to 4 hydroxy groups],

or

-   a cyclopropyl or cyclopentyl ring -   (the cyclopropyl or cyclopentyl ring may be substituted with 1 or 2     groups selected from the group consisting of a hydroxymethyl group,     1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, and     1,2,3,4-tetrahydroxybutyl group),

(7) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein

-   X and Y represent a group in which X and Y together with the carbon     atom of ring B form ring A, and ring A is -   a 3- to 6-membered heterocyclyl ring -   {the heterocyclyl ring is -   oxirane, tetrahydrofuran, -   1,3-dioxolane, 1,3-dioxane, -   1,3-dithiolane, 1,3-dithiane, -   1,3-oxathiolane, or 1,3-oxathiane, -   these heterocyclyl rings may form a fused ring or spiro ring with a     5- or 6-membered heterocyclyl ring (the 5- or 6-membered     heterocyclyl ring is tetrahydrofuran, tetrahydropyran or     1,3-dioxane) or cyclohexyl ring, and

ring A, including the fused ring and spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of Substituent group α [Substituent group α represents a hydroxy group and a group having the formula NR⁶R⁷ (R⁶ and R⁷, independently from each other, represent a hydrogen atom or acetyl group)], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group},

(8) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein

n is 0 or 1, and

R¹ is a hydroxy group, halogen atom, C₁-C₆ alkyl group or C₁-C₆ alkoxy group,

(9) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein

n is 0 or 1, and

R¹ is a fluorine atom or methyl group,

(10) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein n is 0,

(11) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R² is a C₁-C₆ alkyl group,

(12) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R² is a C₁-C₄ alkyl group,

(13) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R² is an ethyl group,

(14) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein

R³ is

a phenyl group which may be substituted with a group selected from Substituent group ε, or

a pyrrolyl group which may be substituted with a group selected from Substituent group ε, and

Substituent group ε is a halogen atom, C₁-C₁₄ alkyl group and halogeno C₁-C₁₄ alkyl group,

(15) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein

R³ is

a phenyl group which may be substituted with a group selected from Substituent group ε, or

a pyrrolyl group which may be substituted with a group selected from Substituent group ε, and

Substituent group ε is a fluorine atom, chlorine atom, bromine atom, C₃-C₈ alkyl group and halogeno C₄-C₈ alkyl group,

(16) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein

R³ is

a phenyl group which may be substituted with a group selected from Substituent group ε, and

Substituent group ε is a fluorine atom, chlorine atom and C₃-C₈ alkyl group,

(17) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R⁵ is a hydrogen atom or C₁-C₆ alkyl group,

(18) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R⁵ is a hydrogen atom or methyl group,

(19) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R⁵ is a hydrogen atom,

(20) The compounds of the following group selected from the aforementioned (1) or pharmacologically acceptable salt thereof:

-   ethyl     8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3-trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, -   ethyl     3-acetylamino-9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, -   ethyl     9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, -   ethyl     8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(hydroxymethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,     and -   ethyl     8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,

(21) A medicament containing the compound or pharmacologically acceptable salt thereof selected from any one of the aforementioned (1) to (20) as an active ingredient,

(22) The medicament according to the aforementioned (21) for use in suppressing intracellular signal transduction or cell activation induced by endotoxin,

(23) The medicament according to the aforementioned (21) for use in suppressing the generation of inflammatory mediators due to intracellular signal transduction or cell activation induced by endotoxin,

(24) The medicament according to the aforementioned (21) for use as a prophylactic or therapeutic agent for a disease due to intracellular signal transduction or cell activation inducted by endotoxin,

(25) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for a disease mediated by an inflammatory mediator, of which generation is induced by endotoxin,

(26) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for a disease mediated by an inflammatory mediator, which is generated due to intracellular signal transduction or cell activation induced by endotoxin,

(27) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for sepsis, and

-   (i) a method of suppressing intracellular signal transduction     induced by endotoxin and suppressing excess generation of     inflammatory mediators such as TNF-α which is induced by the     intracellular signal transduction, and (ii) a method of preventing     and/or treating a disease mediated by intracellular signal     transduction and by an inflammatory mediator which is generated due     to the intracellular signal transduction, comprising administering     an effective amount of the compound according to any one of the     aforementioned (1) to (20) or pharmacologically acceptable salt     thereof to a warm-blood animal (preferably a human).

EFFECTS OF THE INVENTION

The substituted cycloalkene derivative according to the present invention having the general formula (I) has excellent activity to suppress intracellular signal transduction or cell activation induced by endotoxin and to suppress excess generation of inflammatory mediators such as TNF-α due to the intracellular signal transduction and cell activation, and is useful as a medicament, especially as a prophylactic and/or therapeutic agent for ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, sepsis, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis, leukemia and the like, which are induced by the intervention of the intracellular signal transduction or cell activation, and by inflammatory mediators due to the intracellular signal transduction and cell activation.

BEST MODE FOR CARRYING OUT THE INVENTION

“Halogen atom” in the definitions of R¹, Substituent group α, Substituent group β, Substituent group δ and Substituent group ε includes, for example, a fluorine atom, chlorine atom, bromine atom or iodine atom.

With respect to R¹, it is preferably a fluorine atom or chlorine atom, more preferably a fluorine atom.

With respect to Substituent group ε, it is preferably a fluorine atom, chlorine atom or bromine atom, more preferably a fluorine atom or chlorine atom.

“Alkyl group” in the definitions of the NR group which may be included in ring A, substituent of ring A, R¹, R², R⁵, R⁶, R⁷, Substituent group β, Substituent group δ and Substituent group ε includes a linear or branched alkyl group.

“C₁-C₆ alkyl group” of “C₁-C₆ alkyl group which may be substituted with a group selected from Substituent group α” in the definition of the NR group which may be included in ring A; “C₁-C₆ alkyl group” of “cyclopropyl C₁-C₆ alkyl group” in the definition of a substituent of ring A; “C₁-C₆ alkyl group” of “C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α” in the definition of a substituent of ring A; “C₁-C₆ alkyl group” of “C₁-C₆ alkyl group which may be substituted with a group selected from Substituent group β” in the definitions of R² and R⁵; and “C₁-C₆ alkyl group” in the definitions of Substituent group δ, R⁶ and R⁷ are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl group or the like.

Among the “C₁-C₆ alkyl groups”, the one with respect to the NR group which may be included in ring A is preferably methyl.

With respect to a substituent of ring A, it is preferably a C₁-C₄ alkyl group.

With respect to R², it is preferably a C₁-C₄ alkyl group, more preferably ethyl.

With respect to R⁵, it is preferably methyl.

With respect to R⁶ and R⁷, it is preferably methyl.

With respect to Substituent group δ, it is preferably a C₁-C₄ alkyl group.

C₁-C₁₄ alkyl groups of “C₁-C₁₄ alkyl group” and “cyclopropyl C₁-C₁₄ alkyl group” in the definition of Substituent group ε are, for example, the aforementioned “C₁-C₆ alkyl group”, octyl, nonyl, decyl, dodecyl, tetradecyl or the like.

With respect to “C₁-C₁₄ alkyl group” in the definition of Substituent group ε, it is preferably C₃-C₈ alkyl group.

“C₁-C₂₀ alkyl group” in the definition of R¹ is, for example, the aforementioned “C₁-C₁₄ alkyl group”, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl or the like. Preferably, it is a C₁-C₆ alkyl group, and more preferably a methyl group.

“Alkenyl group” in the definitions of the NR group which may be included in ring A, substituent of ring A, R¹, R², R⁵, R⁶, R⁷ and Substituent group α is a linear or branched alkenyl group.

“C₃-C₆ alkenyl group” in the definition of R¹ is, for example, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, preferably a C₃-C₄ alkenyl group.

“C₂-C₆ alkenyl group” of “C₂-C₆ alkenyl group which may be substituted with a group selected from Substituent group α” in the definition of the NR group which may be included in ring A; “C₂-C₆ alkenyl group” of “C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α” in the definition of substituent of ring A; “C₂-C₆ alkenyl group” of “C₂-C₆ alkenyl group which may be substituted with a group selected from Substituent group β” in the definitions of R² and R⁵; and “C₂-C₆ alkenyl group” in the definitions of R⁶ and R⁷ are, for example, vinyl or the aforementioned “C₃-C₆ alkenyl group”, preferably a C₃-C₄ alkenyl group.

“Alkynyl group” in the definitions of the NR group which may be included in ring A, substituent of ring A, R¹, R², R⁵, R⁶, R⁷ and Substituent group α is a linear or branched alkynyl group.

“C₃-C₆ alkynyl group” in the definition of R¹ is, for example, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, preferably a C₃-C₄ alkyl group.

“C₂-C₆ alkynyl group” of “C₂-C₆ alkynyl group which may be substituted with a group selected from Substituent group α” in the definition of the NR group which may be included in ring A; “C₂-C₆ alkynyl group” of “C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group α” in the definition of substituent of ring A; “C₂-C₆ alkynyl group” of “C₂-C₆ alkynyl group which may be substituted with a group selected from Substituent group β” in the definitions of R¹ and R⁵; and “C₂-C₆ alkynyl group” in the definitions of R⁶ and R⁷ are, for example, ethynyl or the aforementioned “C₃-C₆ alkynyl group”, preferably a C₃-C₄ alkynyl group.

“C₃-C₆ cycloalkyl group” in the definitions of Substituent group δ and Substituent group ε are, for example, cyclopropyl, cyclopentyl or cyclohexyl.

“3- to 7-membered cycloalkyl ring” in the definition of ring A may include an unsaturated bond, and such ring is, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane or cycloheptadiene.

The aforementioned “3- to 7-membered cycloalkyl ring” may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and such cycloalkyl ring is, for example, 2-oxa-bicyclo[4,3,0]nonan-8-ylidene, 3-oxa-bicyclo[3,3,0]heptan-7-ylidene, 2,4-dioxa-spiro[6.6]undecan-8-ylidene, bicyclo[4,3,0]nonan-7-ylidene, spiro[6.6]undecan-8-ylidene or the like.

In addition, the aforementioned “3- to 7-membered cycloalkyl ring” may not form a fused ring or spiro ring, and may be substituted with an oxo group or a thioxo group.

With respect to the aforementioned “cycloalkyl ring”, a cycloalkyl ring, fused ring which is fused to the cycloalkyl ring, or spiro ring which is spiro bound to the cycloalkyl ring may be substituted with the same or different 1 to 4 (preferably 1 or 2) groups selected from the group consisting of Substituent group α, cyclopropyl C₁-C₆ alkyl group, C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α, C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α and C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group α.

Preferred examples of the ring are, 3-hydroxycyclopentane, 4-hydroxycyclohexane, 3-hydroxymethylcyclopentane, 3,4-dihydroxymethylcyclopentane, 4-hydroxymethylcyclohexane, 4,4-dihydroxymethylcyclohexane, 3-(1,2-dihydroxyethyl)cyclopentane, 4-(1,2-dihydroxyethyl)cyclohexane, 3,4-bis(1,2-dihydroxyethyl)cyclopentane, 4,4-bis(1,2-dihydroxyethyl)cyclohexane, 3-(1,2,3-trihydroxypropyl)cyclopentane, 4-(1,2,3-trihydroxypropyl)cyclohexane, 3-(1,2,3,4-tetrahydroxybutyl)cyclopentane, 4-(1,2,3,4-tetrahydroxybutyl)cyclohexane, 3-ethoxycarbonylcyclopentane, 4-ethoxycarbonylcyclohexane, 4,4-diethoxycarbonylcyclchexane, 3-carbamoylcyclopentane, 4-carbamoylcyclohexane, 3-acetylaminocyclopentane, 4-acetylaminocyclohexane, 3,4-diacetylaminomethylcyclopentane, 2,3,4,5-tetrahydroxybicyclo[4,3,0]nonane (the binding position with ring B is the 8-position), 3-oxa-bicyclo[3,3,0]octane (the binding position with ring B is the 7-position), 2,4-dihydroxymethyl-3-oxa-bicyclo[3,3,0]octane (the binding position with ring B is the 7-position), and 2,4-dioxaspiro[5.5]undecane (the binding position with ring B is the 9-position).

“Cycloalkyl ring” in the definition of ring A is, among the aforementioned rings, preferably a 3- to 7-membered cycloalkyl ring which may be substituted with 1 or 2 groups selected from a group consisting of a hydroxy group, hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxyethyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group, more preferably a 3- to 5-membered saturated cycloalkyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group, and particularly preferably a cyclopropyl or cyclopentyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group and 1,2,3,4-tetrahydroxybutyl group.

“C₃-C₁₀ cycloalkyl group” in the definition of R¹ is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

“C₄-C₁₂ cycloalkylalkyl group” in the definition of R¹ is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl, preferably a C₄-C₈ cycloalkylalkyl group, more preferably a C₄-C₇ cycloalkylalkyl group.

With respect to “3- to 7-membered heterocyclyl ring” in the definition of ring A, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ group or C₁-C₆ alkylcarbonyl group which may be substituted with a group selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂, preferably any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO, and a group having the formula SO₂. The 3- to 7-membered heterocyclyl ring may include an unsaturated bond.

Examples of such ring are, a heterocyclyl ring including a nitrogen atom such as aziridine, azetidine, pyrrolidine, pyrroline, piperidine and imidazolidine; a heterocyclyl ring including an oxygen atom such as oxirane, oxetane, tetrahydrofuran, oxolene, tetrahydropyran, dihydropyran, oxepane, 1,3-dioxclane, 1,3-dioxane and 1,3-dioxepane; a heterocyclyl ring including a sulfur atom, a group having the formula SO or a group having the formula SO₂ such as thiirane, thietane, thiolane, thiolene, thiane, thiepane, 1,3-dithiolane, 1,3-dithiane, 1,3-dithiepane, 1,3-dioxo-1,3-dithiolane, 1,3-dioxo-1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane and 1,1,3,3-tetraoxo-1,3-dithiane; a heterocyclyl ring including an oxygen atom and a sulfur atom such as 1,3-oxathiolane, 1,3-oxathiane and 1,3-oxathiepane; a heterocyclyl ring including a nitrogen atom and an oxygen atom such as 1,3-oxapyrrolidine and 1,3-oxapyrroline; and a heterocyclyl ring including a nitrogen atom and a sulfur atom such as 1,3-thiapyrrolidine and 1,3-thiapyrroline.

Preferably, it is oxirane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepane.

More preferably, it is oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane or 1,3-oxathiane.

Even more preferably, it is oxirane, 1,3-dioxolane, 1,3-dioxane or 1,3-oxathiolane.

The aforementioned “3- to 7-membered heterocyclyl ring” may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, preferably may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atom) or 5- or 6-membered cycloalkyl ring, and more preferably may form a fused ring or spiro ring with tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, 1,3-dioxane or cyclohexyl ring.

Examples of such heterocyclyl ring are 2,4-dioxa-bicyclo[3,3,0]octane (the binding position with ring B is the 3-position), 2,4,7-trioxa-bicyclo[3,3,0]octane (the binding position with ring B is the 3-position), 7,9-dioxa-bicyclo[4,3,0]nonane (the binding position with ring B is the 8-position), 7-aza-2,4-dioxa-bicyclo[3,3,0]octane (the binding position with ring B is the 3-position), 2,4,8,10-tetraoxaspiro[5,5]undecane (the binding position with ring B is the 3-position) and the like. The binding position of these rings with ring B is the same as the aforedescribed one.

In addition, the aforementioned “3- to 7-membered heterocyclyl ring” may not form a fused ring or spiro ring, and may be substituted with an oxo group or a thioxo group.

With respect to the aforementioned “heterocyclyl ring”, heterocyclyl ring, fused ring which is fused to the heterocyclyl ring or spiro ring which is spiro bound to the heterocyclyl ring may be substituted with the same or different 1 to 4 (preferably 1 or 2) substituents.

The substituent is a group selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆ alkyl group, a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α, a C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α and a C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group α.

The substituent is preferably a group selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆ alkyl group and a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α.

More preferably, it is a group selected from the group consisting of an oxo group, a thioxo group, Substituent group α and a C₁-C₆ alkyl group which may be substituted with 1 to 4 groups selected from Substituent group α.

Even more preferably, it is 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α(Substituent group α is a hydroxy group and a group having the formula NR⁶R⁷, and R⁶ and R⁷, independently from each other, represent a hydrogen atom or C₁-C₆ alkylcarbonyl group), a methyl group, an ethyl group and a C₁-C₆ alkyl group substituted with 1 to 4 hydroxy groups.

Further preferably, it is 1 or 2 groups selected from the group consisting of Substituent group α [Substituent group α represents a hydroxy group and a group having the formula NR⁶R⁷ (R⁶ and R⁷, independently from each other, represent a hydrogen atom or methylcarbonyl group)], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.

As for such examples,

-   oxirane, oxolane, tetrahydrofuran (traditional name, oxolane     according IUPAC nomenclature), tetrahydropyran (traditional name,     oxane according IUPAC nomenclature), 1,3-dioxclane, 1,3-dioxane,     1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane,     1,3-oxathiane, 1,3-oxathiepane, tetrahydrooxazole,     tetrahydro-1,3-oxadine, tetrahydrothiazole, tetrahydro-1,3-thiazine,     1,1,3,3-tetraoxo-1,3-dithiane, 2,4,7-trioxa-bicyclo[3,3,0]octane,     2,4-dithia-7-oxa-bicyclo[3,3,0]octane,     2-thia-4,7-dioxa-bicyclo[3,3,0]octane,     2,4,8,10-tetraoxaspiro[5.5]undecane,     2,4-dithia-8,10-dioxaspiro[5.5]undecane,     2-thia-4,8,10-trioxaspiro[5.5]undecane, 2-hydroxytetrahydrofuran,     4-hydroxy-1,3-dioxolane, 4,5-dihydroxy-1,3-dioxolane,     5-hydroxy-1,3-dioxane, 5,5-dihydroxy-1,3-dioxane,     4-hydroxy-1,3-dithiolane, 4,5-dihydroxy-1,3-dithiolane,     5-hydroxy-1,3-dithiane, 5,5-dihydroxy-1,3-dithiane,     4-hydroxy-1,1,3,3-tetraoxo-1,3-dithiolane,     4,5-dihydroxy-1,1,3,3-tetraoxo-1,3-dithiolane,     4-hydroxy-1,3-oxathiolane, 5-hydroxy-1,3-oxathiane,     5,5-dihydroxy-1,3-oxathiane,     6,8-dihydroxy-2,4-dioxa-bicyclo[3,3,0]octane,     6,8-dihydroxy-2,4,7-trioxa-bicyclo[3,3,0]octane,     2,3,4,5-tetrahydroxy-7,9-dioxa-bicyclo[4,3,0]nonane,     6,8-dihydroxy-7-aza-2,4-dioxa-bicyclo[3,3,0]octane,     9-hydroxy-2,4,8,10-tetraoxaspiro[5.5]undecane,     2,3,4,5-tetrahydro-7,9-dithia-bicyclo[4,3,0]nonane,     2,3,4,5-tetrahydro-7-thia-9-oxa-bicyclo[4,3,0]nonane,     2-carboxytetrahydrofuran, 4-carboxy-1,3-dioxolane,     5-carboxy-1,3-dioxane, 4-carboxy-1,3-dithiolane,     5-carboxy-1,3-dithiane, 4-carboxy-1,1,3,3-tetraoxo-1,3-dithiolane,     4-carboxy-1,3-oxathiolane, 5-carboxy-1,3-oxathiane,     2-methoxycarbonyltetrahydrofuran, 4-methoxycarbonyl-1,3-dioxolane,     5-methoxycarbonyl-1,3-dioxane, 5,5-dimethoxycarbonyl-1,3-dioxane,     4-methoxycarbonyl-1,3-dithiolane, 5-methoxycarbonyl-1,3-dithiane,     5,5-dimethoxycarbonyl-1,3-dithiane,     4-methoxycarbonyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-methoxycarbonyl-1,3-oxathiolane, 5-methoxycarbonyl-1,3-oxathiane,     5,5-dimethoxycarbonyl-1,3-oxathiane,     6,8-dimethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane,     6,8-dimethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane,     6,8-dimethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane,     8-methoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane,     2-ethoxycarbonyltetrahydrofuran, 4-ethoxycarbonyl-1,3-dioxolane,     5-ethoxycarbonyl-1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane,     4-ethoxycarbonyl-1,3-dithiolane, 5-ethoxycarbonyl-1,3-dithiane,     5,5-diethoxycarbonyl-1,3-dithiane,     4-ethoxycarbonyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-ethoxycarbonyl-1,3-oxathiolane, 5-ethoxycarbonyl-1,3-oxathiane,     5,5-diethoxycarbonyl-1,3-oxathiane,     6,8-diethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane,     6,8-diethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane,     6,8-diethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane,     8-ethoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane,     2-aminotetrahydrofuran, 4-amino-1,3-dioxolane,     4,5-diamino-1,3-dioxolane, 5-amino-1,3-dioxane,     4-amino-1,3-dithiolane, 4,5-diamino-1,3-dithiolane,     5-amino-1,3-dithiane, 4-amino-1,1,3,3-tetraoxo-1,3-dithiolane,     4-amino-1,3-oxathiolane, 5-amino-1,3-oxathiane, -   2-acetylaminotetrahydrofuran, 4-acetylamino-1,3-dioxolane,     4,5-bis(acetylamino)-1,3-dioxolane, 5-acetylamino-1,3-dioxane,     4-acetylamino-1,3-dithiolane, 4,5-bis(acetylamino)-1,3-dithiolane,     5-acetylamino-1,3-dithiane,     4-acetylamino-1,1,3,3-tetraoxo-1,3-dithiolane,     4-acetylamino-1,3-oxathiolane, 5-acetylamino-1,3-oxathiane,     6,8-diacetylamino-2,4-dioxa-bicyclo[3,3,0]octane,     6,8-diacetylamino-2,4,7-trioxa-bicyclo[3,3,0]octane,     6,8-diacetylamino-7-aza-2,4-dioxa-bicyclo[3,3,0]octane,     8-acetylamino-2,4,7,9-tetraoxaspiro[5.5]undecane,     2-methyltetrahydrofuran, 4-methyl-1,3-dioxclane,     4,5-dimethyl-1,3-dioxolane, 5-methyl-1,3-dioxane,     4-methyl-1,3-dithiolane, 4,5-dimethyl-1,3-dithiolane,     5-methyl-1,3-dithiane, 4-methyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-methyl-1,3-oxathiolane, 5-methyl-1,3-oxathiane, -   5,5-dimethyl-1,3-dioxane, 5,5-dimethyl-1,3-dithiane,     5,5-dimethyl-1,3-oxathiane, -   2-ethyltetrahydrofuran, 4-ethyl-1,3-dioxolane,     4,5-diethyl-1,3-dioxolane, 5-ethyl-1,3-dioxane,     4-ethyl-1,3-dithiolane, 4,5-diethyl-1,3-dithiolane,     5-ethyl-1,3-dithiane, 4-ethyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-ethyl-1,3-oxathiolane, S-ethyl-1,3-oxathiane, -   2-hydroxymethyltetrahydrofuran, 4-hydroxymethyl-1,3-dioxolane,     5-hydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane,     4-hydroxymethyl-1,3-dithiolane, 5-hydroxymethyl-1,3-dithiane,     5,5-dihydroxymethyl-1,3-dithiane,     4-hydroxymethyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-hydroxymethyl-1,3-oxathiolane, 5-hydroxymethyl-1,3-oxathiane,     5,5-dihydroxymethyl-1,3-oxathiane,     4,5-dihydroxymethyl-1,3-dioxolane,     4,5-dihydroxymethyl-1,3-dithiolane,     4,5-dihydroxymethyl-1,3-oxathiolane,     5,5-dihydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dithiane,     5,5-dihydroxymethyl-1,3-oxathiane,     6,8-dihydroxymethyl-2,4,7-trioxa-bicyclo[3,3,0]octane,     6,8-dihydroxymethyl-2,4-dithia-7-oxa-bicyclo[3,3,0]octane,     6,8-dihydroxymethyl-2-thia-4,7-dioxa-bicyclo[3,3,0]octane,     6-oxo-8-hydroxymethyl-2,4,7-trioxa-bicyclo[3,3,0]octane, -   2-(1,2-dihydroxyethyl)tetrahydrofuran,     4-(1,2-dihydroxyethyl)-1,3-dioxolane,     5-(1,2-dihydroxyethyl)-1,3-dioxane,     5,5-bis(1,2-dihydroxyethyl)-1,3-dioxane,     4-(1,2-dihydroxyethyl)-1,3-dithiolane,     5-(1,2-dihydroxyethyl)-1,3-dithiane,     5,5-bis(1,2-dihydroxyethyl)-1,3-dithiane,     4-(1,2-dihydroxyethyl)-1,1,3,3-tetraoxo-1,3-dithiolane,     4-(1,2-dihydroxyethyl)-1,3-oxathiolane,     5-(1,2-dihydroxyethyl)-1,3-oxathiane,     5,5-bis(1,2-dihydroxyethyl)-1,3-oxathiane, -   4,5-bis(1,2-dihydroxyethyl)-1,3-dioxolane,     4,5-bis(1,2-dihydroxyethyl)-1,3-dithiolane,     4,5-bis(1,2-dihydroxyethyl)-1,3-oxathiolane, -   4,5-bis(1-hydroxyethyl)-1,3-dioxolane,     4,5-bis(1-hydroxypropyl)-1,3-dioxolane, -   2-(1,2,3-trihydroxypropyl)tetrahydrofuran,     4-(1,2,3-trihydroxypropyl)-1,3-dioxolane,     5-(1,2,3-trihydroxypropyl)-1,3-dioxane,     5,5-bis(1,2,3-trihydroxypropyl)-1,3-dioxane,     4-(1,2,3-trihydroxypropyl)-1,3-dithiolane,     5-(1,2,3-trihydroxypropyl)-1,3-dithiane,     5,5-bis(1,2,3-trihydroxypropyl)-1,3-dithiane,     4-(1,2,3-trihydroxypropyl)-1,1,3,3-tetraoxo-1,3-dithiolane,     4-(1,2,3-trihydroxypropyl)-1,3-oxathiolane,     5-(1,2-dihydroxyethyl)-1,3-oxathiane,     5,5-bis(1,2,3-trihydroxypropyl)-1,3-oxathiane, -   2-(1,2,3,4-tetrahydroxybutyl)tetrahydrofuran,     4-(1,2,3,4-tetrahydroxybutyl)-1,3-dioxolane,     5-(1,2,3,4-tetrahydroxybutyl)-1,3-dioxane,     5,5-bis(1,2,3,4-tetrahydroxybutyl)-1,3-dioxane,     4-(1,2,3,4-tetrahydroxybutyl)-1,3-dithiolane,     5-(1,2,3,4-tetrahydroxybutyl)-1,3-dithiane,     5,5-bis(1,2,3,4-tetrahydroxybutyl)-1,3-dithiane,     4-(1,2,3,4-tetrahydroxybutyl)-1,1,3,3-tetraoxo-1,3-dithiolane,     4-(1,2,3,4-tetrahydroxybutyl)-1,3-oxathiolane,     5-(1,2,3,4-tetrahydroxybutyl)-1,3-oxathiane,     5,5-bis(1,2,3,4-tetrahydroxybutyl)-1,3-oxathiane, -   2-acetylaminomethyltetrahydrofuran,     4-acetylaminomethyl-1,3-dioxolane,     4,5-diacetylaminomethyl-1,3-dioxolane,     5-acetylaminomethyl-1,3-dioxane, 4-acetylaminomethyl-1,3-dithiolane,     4,5-diacetylaminomethyl-1,3-dithiolane,     5-acetylaminomethyl-1,3-dithiane,     4-acetylaminomethyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-acetylaminomethyl-1,3-oxathiolane,     5-acetylaminomethyl-1,3-oxathiane, -   4,5-diacetylaminomethyl-1,3-dioxolane,     4,5-diacetylaminomethyl-1,3-dithiolane,     4,5-diacetylaminomethyl-1,3-oxathiolane, 2-vinyltetrahydrofuran,     4-vinyl-1,3-dioxolane, 4,5-divinyl-1,3-dioxolane,     5-vinyl-1,3-dioxane, 4-vinyl-1,3-dithiolane,     4,5-divinyl-1,3-dithiolane, 5-vinyl-1,3-dithiane,     4-vinyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-vinyl-1,3-oxathiolane,     5-vinyl-1,3-oxathiane, -   2-propenyltetrahydrofuran, 4-propenyl-1,3-dioxolane,     4,5-dipropenyl-1,3-dioxolane, 5-propenyl-1,3-dioxane,     4-propenyl-1,3-dithiolane, 4,5-dipropenyl-1,3-dithiolane,     5-propenyl-1,3-dithiane, 4-propenyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-propenyl-1,3-oxathiolane, 5-propenyl-1,3-oxathiane,     2-propynyltetrahydrofuran, 4-propynyl-1,3-dioxolane,     4,5-dipropynyl-1,3-dioxolane, 5-propynyl-1,3-dioxane,     4-propynyl-1,3-dithiolane, 4,5-dipropynyl-1,3-dithiclane,     5-propynyl-1,3-dithiane, 4-propynyl-1,1,3,3-tetraoxo-1,3-dithiolane,     4-propynyl-1,3-oxathiolane and 5-propynyl-1,3-oxathiane can be     mentioned.

“C₆-C₁₀ aryl group” of “C₆-C₁₀ aryl group which may be substituted with a group selected from Substituent group β” in the definition of Substituent group γ; and “C₆-C₁₀ aryl group” in the definitions of Substituent group δ and Substituent group ε are, for example, phenyl or naphthyl.

With respect to the “C₆-C₁₀ aryl group which may be substituted with a group selected from Substituent group β”, the “C₆-C₁₀ aryl group” is substituted with a substituent selected from Substituent group β at a substitutable position, the substituent is not limited to one, and may be the same or different plural (2 to 4) substituents.

“5- or 6-membered heteroaryl group” in the definition of R³ includes 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. As for such heteroaryl, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, piridazinyl, pyrimidinyl and pyradinyl can be mentioned, and it is preferably furyl, thienyl, pyrrolyl, pyridyl or pyrimidinyl, more preferably pyrrolyl.

“5-membered heteroaryl group” in the definitions of Substituent group δ and Substituent group ε is, for example, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl or furyl.

“Halogeno C₁-C₆ alkyl group” in the definition of Substituent group δ is, for example, trifluoromethyl or trifluoroethyl.

“Halogeno C₁-C₁₄ alkyl group” in the definition of Substituent group ε is, for example, the aforementioned “halogeno C₁-C₆ alkyl group”, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 7,7,7-trifluoroheptyl or 8,8,8-trifluorooctyl, preferably a halogeno C₄-C₈ alkyl group.

“C₁-C₆ alkoxy group” in the definitions of Substituent group α, Substituent group β and Substituent group δ represents a group in which an oxygen atom is bound to the aforementioned “C₁-C₆ alkyl group”, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy, preferably a C₁-C₄ alkoxy group, and more preferably C₁-C₂ alkoxy group.

“C₁-C₁₄ alkoxy group” in the definition of Substituent group ε represents a group in which an oxygen atom is bound to the aforementioned “C₁-C₁₄ alkyl group”, for example, the aforementioned “C₁-C₆ alkoxy group”, octyloxy, nonyloxy, decyloxy, dodecyloxy, tetradecyloxy or the like, preferably a C₁-C₁₀ alkoxy group, and more preferably a C₄-C₈ alkoxy group.

“Halogeno C₁-C₆ alkoxy group” in the definitions of Substituent group α and Substituent group δ represents a group in which one or two or more hydrogen atoms of the aforementioned “C₁-C₆ alkyl group” are substituted with the aforementioned “halogen atom”. Preferably, it is a halogeno C₁-C₄ alkoxy group, more preferably difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, and even more preferably trifluoromethoxy.

“Halogeno C₁-C₁₄ alkoxy group” in the definition of Substituent group ε represents a group in which one or two or more hydrogen atoms of the aforementioned “C₁-C₁₄ alkyl group” are substituted with the aforementioned “halogen atom”. Preferably, it is a halogeno C₁-C₁₀ alkoxy group, more preferably a halogeno C₄-C₈ alkoxy group, and even more preferably 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 7,7,7-trifluoroheptyloxy or 8,8,8-trifluorooctyloxy.

“C₃-C₁₀ cycloalkyloxy group” in the definition of Substituent group γ is, for example, cyclopropyloxy, cyclohexyloxy or the like.

“C₆-C₁₀ aryloxy group” in the definition of Substituent group γ is, for example, phenoxy or naphthyloxy.

“C₇-C₁₉ aralkyloxy group” in the definition of Substituent group γ is, for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy or 1-naphthylmethyloxy.

“C₁-C₆ alkylthio group” in the definitions of Substituent group β and Substituent group δ represents a group in which a sulfur atom is bound to the aforementioned “C₁-C₆ alkyl group”, and the sulfur atom may be oxidized. Preferably, it is a C₁-C₄ alkylthio group, for example, methylthio, ethylthio, n-propylthio, n-butylthio, methylsulfinyl or methylsulfonyl.

With respect to “C₁-C₁₄ alkylthio group” in the definition of Substituent group ε, the sulfur atom to which the alkyl group is bound may be oxidized, and it is for example, the aforementioned “C₁-C₆ alkylthio group”, n-heptylthio, 3-methylhexylthio, n-octylthio, 2,4-dimethylhexylthio, n-octylthio, or 2,3,6-trimethylheptylthio, preferably a C₁-C₁₀ alkylthio group, and more preferably a C₄-C₈ alkylthio group.

With respect to “C₃-C₁₀ cycloalkylthio group” in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl or cyclohexylsulfonyl.

With respect to “C₆-C₁₀ arylthio group” in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, phenylthio, naphthylthio, phenylsulfinyl or phenylsulfonyl.

With respect to “C₇-C₁₉ aralkylthio group” in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl or benzylsulfonyl.

“C₁-C₆ alkanoyl group” in the definitions of R⁶, R⁷, Substituent group β and Substituent group δ represents a group in which a hydrogen atom or C₁-C₅ alkyl group is bound to a carbonyl group, and is for example, formyl, acetyl, propionyl, butyryl, valeryl or pyvaloyl.

“C₁-C₁₄ alkanoyl group” in the definition of Substituent group ε is, for example, the aforementioned “C₁-C₆ alkanoyl group”, octanoyl, decanoyl, dodecanoyl or tetradecanoyl.

“C₂-C₄ alkenyl-carbonyl group” in the definition of Substituent group β is, for example, acryloyl or crotonoyl.

“C₂-C₆ alkenyl-carbonyl group” in the definitions of R⁶ and R⁷ is, for example, the aforementioned “C₂-C₄ alkenyl-carbonyl group”, 1,3-butadienylcarbonyl or 3-methyl-2-butenylcarbonyl.

“C₆-C₁₀ aryl-carbonyl group” in the definition of Substituent group γ is, for example, benzoyl, naphthoyl or phenylacetyl.

“C₁-C₆ alkoxy-carbonyl group” in the definitions of Substituent group α and Substituent group δ represents a group in which the aforementioned “C₁-C₆ alkoxy group” is bound to a carbonyl group, and is for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl or the like.

“C₁-C₁₀ alkoxy-carbonyl group” in the definition of Substituent group β is, for example, the aforementioned “C₁-C₆ alkoxycarbonyl group”, heptyloxy, octyloxy, nonyloxy or decyloxy.

“C₁-C₁₄ alkoxy-carbonyl group” in the definition of Substituent group ε is, for example, the aforementioned “C₁-C₁₀ alkoxy-carbonyl group”, dodecyloxycarbonyl or tetradecyloxycarbonyl, preferably a C₁-C₁₀ alkoxy-carbonyl group, and more preferably a C₄-C₈ alkoxy-carbonyl group.

“C₃-C₆ cycloalkyloxycarbonyl group” in the definition of Substituent group γ is, for example, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or norbornyloxycarbonyl.

“C₆-C₁₀ aryloxy-carbonyl group” in the definition of Substituent group γ is, for example, phenoxycarbonyl or naphthyloxycarbonyl.

“C₇-C₁₉ aralkyloxy-carbonyl group” in the definition of Substituent group γ is, for example, benzyloxycarbonyl, benzhydryloxycarbonyl or 2-phenethyloxycarbonyl.

“C₂-C₆ alkanoyloxy group” in the definition of Substituent group β represents a group in which the C₂-C₆ alkanoyl group is bound to an oxygen atom, and is for example, acetoxy, propionyloxy, butyryloxy, valeryloxy or pivaloyloxy.

“C₁-C₁₀ alkoxy-carbonyloxy group” in the definition of Substituent group β is, for example, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n-pentyloxycarbonyloxy or n-hexyloxycarbonyloxy.

“C₆-C₁₀ aryl-carbonyloxy group” in the definition of Substituent group γ is, for example, benzoyloxy, naphthyloxy or phenylacetoxy.

“Carbamoyl group which may be substituted with a group selected from a C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆ alkanoyl group or C₂-C₆ alkenyl-carbonyl group” in the definition of Substituent group α is a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from C₁-C₆ alkyl groups such as methyl, ethyl, propyl and the like, C₂-C₆ alkenyl groups such as vinyl, allyl, isopropenyl and the like, C₂-C₆ alkynyl groups such as ethynyl and the like, C₁-C₆ alkanoyl groups such as acetyl and the like, and C₂-C₆ alkenyl-carbonyl groups such as acryloyl and the like, preferably, specifically for example, a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from a C₁-C₆ alkyl group and a C₁-C₆ alkanoyl group, more preferably a carbamoyl group or cyclic aminocarbonyl group which is substituted with 1 or 2 C₁-C₂ alkanoyl groups. Specifically, it is carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or N-acetylcarbamoyl, preferably N-acetyl carbamoyl.

“Carbamoyl group which may be substituted with a group selected from a C₁-C₄ alkyl group, phenyl group, C₁-C₇ acyl group and C₁-C₄ alkoxyphenyl group” in the definition of Substituent group β is a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from C₁-C₄ alkyl groups such as methyl, ethyl and the like, phenyl group, C₁-C₇ acyl groups such as acetyl, propionyl, benzoyl and the like, and C₁-C₄ alkoxyphenyl groups such as methoxyphenyl and the like, specifically for example, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperadinylcarbonyl or morpholinocarbonyl.

“Thiocarbamoyl group which may be substituted with a C₁-C₄ alkyl group or phenyl group” in the definition of Substituent group β is a thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from C₁-C₄ alkyl groups such as methyl, ethyl and the like, and a phenyl group, specifically for example, thiocarbamoyl, N-methylthiocarbamoyl or N-phenylthiocarbamoyl.

“Carbamoyloxy group which may be substituted with a C₁-C₄ alkyl group or phenyl group” in the definition of Substituent group β is a carbamoyloxy group which may be substituted with 1 or 2 substituents selected from C₁-C₄ alkyl groups such as methyl, ethyl and the like, and a phenyl group, specifically for example, carbamoyloxy, N-methyl carbamoyloxy, N,N-dimethyl carbamoyloxy, N-ethylcarbamoyloxy or N-phenyl carbamoyloxy.

With respect to “group having the formula NR⁶R⁷” in the definitions of Substituent group α, Substituent group δ and Substituent group ε, R⁶ and R⁷, independently from each other, represent a hydrogen atom, C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆ alkanoyl group or C₂-C₆ alkenyl-carbonyl group, or, together with the nitrogen atom to which R⁶ and R⁷ are bound, form a heterocyclyl group. Preferably, it is a group in which R⁶ and R⁷ are a hydrogen atom, C₁-C₆ alkyl group or C₁-C₆ alkanoyl group, more preferably a group in which R⁶ and R⁷ are a hydrogen atom, C₁-C₄ alkyl group or C₁-C₄ alkanoyl group, even more preferably a group in which R⁶ and R⁷ are a hydrogen atom or C₁-C₂ alkanoyl group. Specifically it is amino, methylamino, ethylamino, dimethylamino, diethylamino or acetylamino, preferably acetylamino.

“C₁-C₆ alkanoylamino group” in the definitions of Substituent group β and Substituent group δ is, for example, acetamide, propionamide, butyramide, valeroamide or pivaloamide.

“C₁-C₁₄ alkanoylamino group” in the definition of Substituent group ε is, for example, the aforementioned “C₁-C₆ alkanoylamino group”, octanoylamino, decanoylamino, dodecanoylamino or tetradecanoylamino.

“C₁-C₁₀ alkoxy-carboxamide group” in the definition of Substituent group β is, for example, methoxycarboxamide, ethoxycarboxamide or tert-butoxycarboxamide.

“Ureido group which may be substituted with a C₁-C₄ alkyl group or phenyl group” in the definition of Substituent group β is, for example, an ureido group which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from C₁-C₄ alkyl groups such as a methyl group, ethyl group and the like, and a phenyl group, and it is for example, ureido, 1-methylureido, 3-methylureido, 3,3-dimethylureido, 1,3-dimethylureido or 3-phenylureido.

“C₆-C₁₀ aryl-carbonylamino group” in the definition of Substituent group γ is, for example, benzamide, naphthoamide or phthalimide.

“C₆-C₁₀ aryloxy-carboxamide group” in the definition of Substituent group γ is, for example, phenoxycarboxamide.

“C₇-C₁₉ aralkyloxy-carboxamide group” in the definition of Substituent group γ is, for example, benzyloxycarboxamide or benzhydryloxycarboxamide.

“C₃-C₁₀ cycloalkyloxy-carbonyloxy group” in the definition of Substituent group γ is, for example, cyclopropyloxycarbonyloxy or cyclohexyloxycarbonyloxy.

“C₆-C₁₀ aryloxy-carbonyloxy group” in the definition of Substituent group γ is, for example, phenoxycarbonyloxy or naphthyloxycarbonyloxy.

“C₇-C₁₉ aralkyloxy-carbonyloxy group” in the definition of Substituent group γ is, for example, benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy or benzhydryloxycarbonyloxy.

“Heterocyclyl group” in the definition of Substituent group γ; and “heterocyclyl group” of “heterocyclyloxy group”, “heterocyclylthio group”, “heterocyclylsulfinyl group”, “heterocyclylsulfonyl group” and “heterocyclyloxycarbonyl group” represent a 5- to 8-membered ring (preferably 5- or 6-membered ring) group or a fused ring group thereof, which contains 1 to several (preferably 1 to 4) hetero atoms such as nitrogen atoms (may be oxidized), oxygen atoms and sulfur atoms. Examples of such “heterocyclyl group” are pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, pyranyl, thiopyranyl, dioxynyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthylidyl group, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl and dioxanyl.

These heterocyclyl groups may be substituted at substitutable positions with 1 to 3 substituents selected from C₁-C₄ alkyl groups such as methyl, ethyl and the like, a hydroxy group, an oxo group and C₁-C₄ alkoxy groups such as methoxy, ethoxy and the like.

“C₁-C₆ alkyl-carbamoyl group” in the definition of Substituent group δ is, for example, methylcarbamoyl, dimethylcarbamoyl or propylcarbamoyl.

“C₁-C₁₄ alkyl-carbamoyl group” in the definition of Substituent group ε is, for example, the aforementioned “C₁-C₆ alkyl-carbamoyl group”, octylcarbamoyl, decylcarbamoyl, dodecylcarbamoyl or tetradecylcarbamoyl, preferably a C₁-C₁₀ alkyl-carbamoyl group, and more preferably a C₄-C₈ alkyl-carbamoyl group.

“C₁-C₆ alkoxy-carbonyl C₁-C₆ alkyl-carbamoyl group” in the definition of Substituent group δ is, for example, butoxycarbonylmethylcarbamoyl or ethoxycarbonylmethylcarbamoyl.

“C₁-C₁₄ alkoxy-carbonyl C₁-C₁₄ alkyl-carbamoyl group” in the definition of Substituent group ε is, for example, the aforementioned “C₁-C₆ alkoxy-carbonyl C₁-C₆ alkyl-carbamoyl group” or octyloxycarbonylmethylcarbamoyl, preferably a C₁-C₁₀ alkoxy-carbonyl C₁-C₁₀ alkyl-carbamoyl group, and more preferably a C₄-C₈ alkoxy-carbonyl C₄-C₈ alkyl-carbamoyl group.

“1,3-diacylguanidino C₁-C₆ alkyl group” in the definition of Substituent group δ is, for example, 1,3-diacetylguanidinomethyl or 1,3-bis-tert-butoxycarbonylguanidinomethyl.

“1,3-diacylguanidino C₁-C₁₄ alkyl group” in the definition of Substituent group ε is, for example, the aforementioned “1,3-diacylguanidino C₁-C₆ alkyl group”, 1,3-diacetylguanidinooctyl or 1,3-bis-tert-butoxycarbonylguanidinooctyl, preferably a 1,3-diacylguanidino C₁-C₁₀ alkyl group, and more preferably a 1,3-diacylguanidino C₄-C₈ alkyl group.

X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, respectively represent a hydrogen atom, or X and Y together represent a substituent of ring B (the substituent is an oxo group or a thioxo group), and preferably represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, or respectively represent a hydrogen atom.

In a preferred example, in the case where X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, ring A is a 3- to 7-membered heterocyclyl ring or 3- to 7-membered saturated cycloalkyl ring.

With respect to the heterocyclyl ring, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom, a C₁-C₆ alkyl group which may be substituted with a group selected from Substituent group α, a C₂-C₆ alkenyl group which may be substituted with a group selected from Substituent group α, a C₂-C₆ alkynyl group which may be substituted with a group selected from Substituent group α or a C₁-C₆ alkanoyl group which may be substituted with a group selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂,

-   may form a fused ring or spiro ring with a 5- or 6-membered     heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen     and/or nitrogen atoms as hetero atom) or 5- or 6-membered cycloalkyl     ring, -   either ring of the heterocyclyl ring, or the fused ring which is     fused to the heterocyclyl ring or the spiro ring which is spiro     bound to the heterocyclyl ring, may be substituted with the same or     different 1 to 4 groups selected from the group consisting of an oxo     group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆     alkyl group and a C₁-C₆ alkyl group which may be substituted with 1     to 5 groups selected from Substituent group α.

The 3- to 7-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxy group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group and an acetylamino group.

Ring A is, more preferably, a 3- to 7-membered heterocyclyl ring or 3- to 5-membered cycloalkyl ring.

With respect to the heterocyclyl ring which is a more preferred example of ring A, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂,

-   may form a fused ring or spiro ring with a 5- or 6-membered     heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen     and/or nitrogen atoms as hetero atom) or 5- or 6-membered cycloalkyl     ring, and -   either ring of the heterocyclyl ring, or the fused ring which is     fused to the heterocyclyl ring or the spiro ring which is spiro     bound to the heterocyclyl ring, may be substituted with the same or     different 1 to 4 groups selected from an oxo group, a thioxo group,     Substituent group α and a C₁-C₆ alkyl group which may be substituted     with 1 to 4 groups selected from Substituent group α.

The 3- to 5-membered cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group and an acetylamino group.

Ring A is, more preferably, the heterocyclyl ring or the undermentioned cyclopropyl or cyclopentyl ring described below.

Examples of such heterocyclyl ring are,

-   oxirane, tetrahydrofuran, tetrahydropyrane, -   1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, -   1,3-dithiolane, 1,3-dithiane, -   1,1,3,3-tetraoxo-1,3-dithiolane, -   1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepane, -   these heterocyclyl rings may form a fused ring or spiro ring with a     5- or 6-membered heterocyclyl ring (the heterocyclyl ring is     tetrahydrofuran, tetrahydropyrane, pyrrolidine, piperidine or     1,3-dioxane) or cyclohexyl ring, -   either ring of the heterocyclyl ring, or the fused ring which is     fused to the heterocyclyl ring or the spiro ring which is spiro     bound to the heterocyclyl ring, may be substituted with 1 or 2     groups selected from the group consisting of an oxo group, a thioxo     group, Substituent group α (Substituent group α represents a hydroxy     group and a group having the formula NR⁶R⁷, and R⁶ and R⁷,     independently from each other, represent a hydrogen atom or a C₁-C₆     alkanoyl group), a methyl group, an ethyl group and a C₁-C₆ alkyl     group which is substituted with 1 to 4 hydroxy groups.

In addition, the cyclopropyl or cyclopentyl ring is a cyclopropyl or cyclopentyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.

Ring A is, further preferably for example,

-   oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane,     1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane or 1,3-oxathiane,     these heterocyclyl rings may form a fused ring or spiro ring with a     5- or 6-membered heterocyclyl ring (the heterocyclyl ring is     tetrahydrofuran, tetrahydropyrane or 1,3-dioxane) or cyclohexyl     ring, and -   either ring of the heterocyclyl ring, or the fused ring which is     fused to the heterocyclyl ring or the spiro ring which is spiro     bound to the heterocyclyl ring, may be substituted with 1 or 2     groups selected from the group consisting of Substituent group α     [Substituent group α represents a hydroxy group and a group having     the formula NR⁶R⁷ (R⁶ and R⁷, independently from each other,     represent a hydrogen atom or acetyl group)], a methyl group, an     ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a     1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.

Ring A is, particularly preferably,

-   oxirane, 1,3-dioxolane, 1,3-dioxane or 1,3-oxathiolane, these     heterocyclyl rings may form a fused ring or spiro ring with a 5- or     6-membered heterocyclyl ring (the heterocyclyl ring is     tetrahydrofuran, tetrahydropyrane or 1,3-dioxane) or cyclohexyl     ring, and -   either ring of the heterocyclyl ring, or the fused ring which is     fused to the heterocyclyl ring or the spiro ring which is spiro     bound to the heterocyclyl ring may be substituted with 1 or 2 groups     selected from the group consisting of Substituent group α     [Substituent group α represents a hydroxy group and a group having     the formula NR⁶R⁷ (R⁶ and R⁷, independently from each other,     represent a hydrogen atom or acetyl group)], a methyl group, a     hydroxymethyl group, a 1,2-dihydroxyethyl group, a     1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.

Preferred specific examples of ring A are,

-   cyclopropyl, 1-hydroxymethylcyclopropyl, 1,2-dihydroxymethyl     cyclopropyl, cyclopentyl, 2-hydroxymethylcyclopentyl,     2,3-dihydroxymethylcyclopentyl,     2,3-bis(1,2-dihydroxyethyl)cyclopentyl,     2-(1,2-dihydroxyethyl)cyclopentyl,     2-(1,2,3-trihydroxypropyl)cyclopentyl,     2-(1,2,3,4-tetrahydroxybutyl)cyclopentyl, -   oxirane, tetrahydrofuran, tetrahydropyrane, 1,3-dioxolane,     1,3-dioxane, 1,3-oxathiolane, 4-hydroxymethyl-1,3-dioxolane,     4,5-dihydroxymethyl-1,3-dioxolane,     4,5-bis(1,2-dihydroxyethyl)-1,3-dioxolane,     4-(1,2-dihydroxyethyl)-1,3-dioxolane,     4-(1,2,3-trihydroxypropyl)-1,3-dioxolane,     4-(1,2,3,4-tetrahydroxybutyl)-1,3-dioxolane,     4,5-diacetylaminomethyl-1,3-dioxolane, 5-hydroxy-1,3-dioxane,     5,5-dihydroxymethyl-1,3-dioxane, 5-acetylamino-1,3-dioxane,     5,5-diethoxycarbonyl-1,3-dioxane and     2,4,7,9-tetraoxaspiro[5.5]undecane, -   more preferred specific examples are, 4-hydroxymethyl-1,3-dioxolane,     4,5-dihydroxymethyl-1,3-dioxolane,     4,5-bis(1,2-dihydroxyethyl)-1,3-dioxolane,     4-(1,2-dihydroxyethyl)-1,3-dioxolane,     4-(1,2,3-trihydroxypropyl)-1,3-dioxolane,     4-(1,2,3,4-tetrahydroxybutyl)-1,3-dioxolane,     4,5-diacetylaminomethyl-1,3-dioxolane, 5-hydroxy-1,3-dioxane,     5-acetylaminc-1,3-dioxane and 5,5-dihydroxymethyl-1,3-dioxane.

Ring B is a 5- to 7-membered cycloalkene group. Here, l and m, which are parameters to determine the number of members of ring B, independently from each other, are an integer of 0 to 3, and l+m is 1 to 3. The l+m being 1 to 3 represents that ring B is 5- to 7-membered. Preferably, 1 is 0, and m is an integer of 1 to 3. More preferably, it is a cyclohexynyl group in which l is 0, and m is 1.

Among the groups defined as R¹, preferred is a hydroxy group, halogen atom, C₁-C₆ alkyl group or C₁-C₆ alkoxy group, more preferred is a hydroxy group, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, methoxy group or ethoxy group, further preferred is a fluorine atom or methyl group.

The number of substitutions n, which is the number of R¹ that are substituted to ring B, is 0 to 3, preferably 0 or 1. More preferably, n is 0.

Among the groups defined as R², preferred is a C₁-C₆ alkyl group which may be substituted with a group selected from Substituent group β, more preferred is a C₁-C₆ alkyl group, further preferred is a C₁-C₄ alkyl group, and particularly preferred is an ethyl group.

Among the groups defined as R³, “5- or 6-membered heteroaryl group” of “5- or 6-membered heteroaryl group which may be substituted with a group selected from Substituent group ε” is particularly preferably a pyrrolyl group. That is, preferably R³ is a phenyl or pyrrolyl group which may be substituted with a group selected from Substituent group ε. Preferably, it is a phenyl or pyrrolyl group which may be substituted with a group selected from a halogen atom, C₁-C₁₄ alkyl group and halogeno C₁-C₁₄ alkyl group, more preferably a phenyl or pyrrolyl group which may be substituted with a group selected from a fluorine atom, chlorine atom, C₁-C₁₀ alkyl group, halogeno C₁-C₁₀ alkyl group and cyclopropyl C₁-C₁₀ alkyl group, even more preferably a phenyl or pyrrolyl group which may be substituted with a group selected from a fluorine atom, chlorine atom, bromine atom, C₃-C₈ alkyl group and halogeno C₄-C₈ alkyl group, and further preferably a phenyl group which may be substituted with a group selected from a fluorine atom, chlorine atom and C₃-C₈ alkyl group.

In addition, in the case where it is substituted by a substituent, the position of substitution is preferably the 2-position or 4-position.

R³ is, for example,

-   a phenyl group, halogenophenyl group, C₁-C₁₄ alkylphenyl group,     cyclopropyl C₁-C₁₄ alkylphenyl group, C₁-C₁₄ alkoxyphenyl group,     C₁-C₁₄ alkoxycarbonylphenyl group, carboxylphenyl group, nitrophenyl     group, cyanophenyl group, halogeno C₁-C₄ alkylphenyl group, halogeno     C₁-C₁₄ alkoxyphenyl group, C₁-C₁₄ alkanoylphenyl group, phenyl group     which is substituted with a 5-membered heteroaryl group, C₁-C₁₄     alkoxy-carbonyl-C₁-C₁₄ alkyl-carbamoylphenyl group,     1,3-diacylguanidino-C₁-C₁₄ alkylphenyl group, phenyl group which is     substituted with a halogen and C₁-C₁₄ alkyl, phenyl group which is     substituted with a halogen and C₁-C₁₄ alkoxycarbonyl, phenyl group     which is substituted with a halogen and cyano, phenyl group which is     substituted with a halogen and a 5-membered heteroaryl group, phenyl     group which is substituted with a halogen and C₁-C₁₄     alkoxy-carbonyl-C₁-C₁₄ alkyl-carbamoyl, -   pyrrolyl group, halogenopyrrolyl group, C₁-C₁₄ alkylpyrrolyl group,     cyclopropyl C₁-C₁₄ alkylpyrrolyl group, C₁-C₁₄ alkoxypyrrolyl group,     C₁-C₁₄ alkoxycarbonylpyrrolyl group, carboxylpyrrolyl group,     nitropyrrolyl group, cyanopyrrolyl group, halogeno C₁-C₁₄     alkylpyrrolyl group, halogeno C₁-C₁₄ alkoxypyrrolyl group, C₁-C₁₄     alkanoylpyrrolyl group, pyrrolyl group which is substituted with a     5-membered heteroaryl group, C₁-C₁₄ alkoxy-carbonyl-C₁-C₁₄     alkyl-carbamoylpyrrolyl group, 1,3-diacylguanidino-C₁-C₁₄     alkylpyrrolyl group, pyrrolyl group which is substituted with a     halogen and C₁-C₁₄ alkyl, pyrrolyl group which is substituted with a     halogen and C₁-C₁₄ alkoxycarbonyl, pyrrolyl group which is     substituted with a halogen and cyano, pyrrolyl group which is     substituted with a halogen and a 5-membered heteroaryl group,     pyrrolyl group which is substituted with a halogen and C₁-C₁₄     alkoxy-carbonyl-C₁-C₁₄ alkyl-carbamoyl, or the like.

Among them, specific examples are preferably,

-   phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl,     3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl,     2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dichlorophenyl,     2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl,     3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,     2,4-dibromophenyl, 2,6-dibromophenyl, 4-chloro-2-fluorophenyl,     2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl,     2-bromo-4-fluorophenyl, 3-chloro-4-fluorophenyl,     2-bromo-4-chlorophenyl, 5-chloro-2-fluorophenyl,     4-bromo-2-chlorophenyl, 2-chloro-6-fluorophenyl,     2,4-dimethoxyphenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl,     2,4,6-trifluorophenyl, 2-chloro-4,6-difluorophenyl,     2,6-dichloro-4-fluorophenyl, 2-bromo-6-chloro-4-fluorophenyl,     2-methylphenyl, 2-ethylphenyl, 2-(n-propyl)phenyl,     2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n-hexyl)phenyl,     2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n-nonyl)phenyl,     2-(n-decyl)phenyl, 2-(n-undecyl)phenyl, 2-(n-dodecyl)phenyl,     2-(n-tridecyl)phenyl, 2-(n-tetradecyl)phenyl, 2-ethynylphenyl,     2-isopropylphenyl, 2-t-butylphenyl, 2-sec-butylphenyl, -   2-methoxyphenyl, 2-ethoxyphenyl, 2-difluoromethoxyphenyl,     2-methylsulfanylphenyl, 2-acetylphenyl, 2-benzylphenyl,     2-(morpholin-4-yl)phenyl, 2-[2-(pyridine-4-yl)ethyl]phenyl,     2-[2-(t-butoxycarbonylamino)ethyl]phenyl, 2-aminophenyl,     2,6-diisopropylphenyl, 2-chloro-4-methylphenyl,     4-fluoro-3-trifluoromethylphenyl, 4-fluoro-3-methoxyphenyl,     4-chloro-2-methoxycarbonylphenyl, 2-fluoro-4-methoxyphenyl,     4-chloro-2-methylphenyl, 2-fluoro-4-methylphenyl,     2-fluoro-5-methylphenyl, 2-chloro-4-methylphenyl,     2-chloro-6-methylphenyl, 4-t-butyl-2-chlorophenyl,     2-bromo-4-isopropylphenyl, 4-chloro-2-methoxy-5-methylphenyl,     4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,     4-fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl,     4-fluoro-2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl,     4-fluoro-2-(n-heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl,     4-fluoro-2-(n-nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl,     4-fluoro-2-(n-undecyl)phenyl, 2-(n-dodecyl)-4-fluorophenyl,     4-fluoro-2-(n-tridecyl)phenyl, 4-fluoro-2-(n-tetradecyl)phenyl,     2-trifluoromethylphenyl, 2-(2,2,2-trifluoroethyl)phenyl,     2-(3,3,3-trifluoropropyl)phenyl, 2-(4,4,4-trifluorobutyl)phenyl,     2-(5,5,5-trifluoropentyl)phenyl, 2-(6,6,6-trifluorohexyl)phenyl,     2-(7,7,7-trifluoroheptyl)phenyl, 2-(8,8,8-trifluorooctyl)phenyl,     2-(9,9,9-trifluorononyl)phenyl, 2-(10,10,10-trifluorodecyl)phenyl,     2-cyclopropylethylphenyl, 2-[3-cyclopropyl-(n-propyl)]phenyl,     2-[4-cyclopropyl-(n-butyl)]phenyl,     2-[5-cyclopropyl-(n-pentyl)]phenyl,     2-[6-cyclopropyl-(n-hexyl)]phenyl,     2-[7-cyclopropyl-(n-heptyl)]phenyl,     2-[8-cyclopropyl-(n-octyl)]phenyl, pyrrolyl, 2-fluoropyrrolyl,     2-chloropyrrolyl, 2-bromopyrrolyl, 2,5-difluoropyrrolyl,     2,5-dichloropyrrolyl, 2,5-dibromopyrrolyl,     2-chloro-5-fluoropyrrolyl, 2-methylpyrrolyl, 2-ethylpyrrolyl,     2-(n-propyl)pyrrolyl, 2-(n-butyl)pyrrolyl, 2-(n-pentyl)pyrrolyl,     2-(n-hexyl)pyrrolyl, 2-(n-heptyl)pyrrolyl, 2-(n-octyl)pyrrolyl,     2-(n-nonyl)pyrrolyl and 2-(n-decyl)pyrrolyl,     more preferably, -   2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodo phenyl,     4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,     2-chloro-4-fluorophenyl, 2-bromo-4-fluorophenyl,     3-chloro-4-fluorophenyl, 2-bromo-4-chlorophenyl,     2,4-dimethoxyphenyl, 2-chloro-4,6-difluorophenyl,     2,6-dichloro-4-fluorophenyl, 2-bromo-6-chloro-4-fluorophenyl,     2-methylphenyl, 2-ethylphenyl, 2-(n-propyl)phenyl,     2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n-hexyl)phenyl,     2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n-nonyl)phenyl,     2-(n-decyl)phenyl, -   2-ethynylphenyl, 2-sec-butylphenyl, 2-methoxyphenyl,     2-methylsulfanylphenyl, 2-benzylphenyl,     2-[2-(t-butoxycarbonylamino)ethyl]phenyl, 4-chloro-2-methylphenyl,     2-fluoro-5-methylphenyl, 2-chloro-4-methylphenyl,     2-chloro-6-methylphenyl, 4-chloro-2-methoxy-5-methylphenyl,     4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,     4-fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl,     4-fluoro-2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl,     4-fluoro-2-(n-heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl,     4-fluoro-2-(n-nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl,     2-(n-butyl)pyrrolyl, 2-(n-pentyl)pyrrolyl, 2-(n-hexyl)pyrrolyl,     2-(n-heptyl)pyrrolyl and 2-(n-octyl)pyrrolyl, and     even more preferably, -   2-chlorophenyl, 2-bromophenyl, 2,4-difluorophenyl,     2-chloro-4-fluorophenyl, 2-bromo-4-fluorophenyl, 2-(n-pentyl)phenyl,     2-(n-hexyl)phenyl, 2-(n-heptyl)phenyl, 2-chloro-6-methylphenyl,     4-fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl,     4-fluoro-2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl,     4-fluoro-2-(n-heptyl)phenyl and 4-fluoro-2-(n-octyl)phenyl.

With respect to the “pharmacologically acceptable salts thereof”, since the compound having the general formula (I) of the present invention can be converted to a salt by reaction with an acid in the case where it has a basic group such as an amino group, or by reaction with a base in the case where it has an acidic group such as a carboxyl group, salts thereof are represented.

Salts of a basic group are preferably inorganic acid salts such as hydrohalogenic acid salts including hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates, phosphates or the like; lower alkanesulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, arylsulfonic acid salts such as benzene sulfonate and p-toluenesulfonate, organic acid salts such as acetate, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates or the like; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate,

On the other hand, salts of an acidic group are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt, amine salts including organic salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt and tris(hydroxymethyl)aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate.

The compounds having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof have an asymmetric carbon atom in their molecules, and thus stereoisomers of R configuration and S configuration exist. Each of them, or a compound with an arbitrary ratio of these, is also included in the present invention. With respect to such stereoisomers, the compound (I) can be synthesized by using an optically resolved starting compound, or a synthesized compound (I) can be optically resolved by ordinary optical resolution or separation methods if desired.

There exist optical isomers with respect to the compound having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof, and each of the optical isomers and mixtures of such isomers are also included in the present invention.

When the compound having the general formula (I) and pharmacologically acceptable salts thereof are exposed to the atmosphere or are recrystallized, they may absorb moisture, resulting in cases such as the adhesion of adsorbed water and the generation of hydrates. Such hydrated compounds and salts are also included in the present invention.

As representative compounds of the present invention, the compounds listed in the following Tables 1 to 3 can be mentioned for example, but the present invention is not limited to these compounds.

Abbreviations and “ring 1” to “ring 21” in the tables are as follows.

-   Ac: acetyl -   Boc: butoxycarbonyl -   Bn: benzyl -   nBu: n-butyl -   sBu: sec-butyl -   tBu: tert-butyl -   cBu: cyclobutylidene -   ndec: n-decane -   Flu: fluoren-1-yl -   cPent: cyclopentylidene -   cPr: cyclopropylidene -   cPrl: cyclopropyl -   cHept: cycloheptylidene -   cHex: cyclohexylidene -   dioxa: 1,3-dioxan-2-ylidene -   dioxe: 1,3-dioxepan-2-ylidene -   dioxo: 1,3-dioxolan-2-ylidene -   dithia: 1,3-dithian-2-ylidene -   dithio: 1,3-dithiolan-2-ylidene -   Et: ethyl -   HB: 1,2,3,4-tetrahydroxybutyl -   HE: 1,2-dihydroxyethyl -   nHept: n-heptyl -   nHex: n-hexyl -   HM: hydroxymethyl -   HP: 1,2,3-trihydroxypropyl -   Me: methyl -   Mor: morpholino -   nNon: n-nonane -   O=: oxo -   nOct: n-octyl -   nPent: n-pentyl -   Ph: phenyl -   NPr: n-propyl -   Pyr: pyrrolyl -   Pyrd: pyridyl -   S=: thioxo -   oxa: 2-oxanylidene -   oxathia: 1,3-oxathian-2-ylidene -   oxathio: 1,3-oxathiolan-2-ylidene -   oxe: 2-oxetanylidene -   oxi: 2-oxiranylidene -   oxo: 2-oxolanylidene -   ozl: tetrahydrooxazol-2-ylidene -   ozn: tetrahydro-1,3-oxadin-2-ylidene -   tzl: tetrahydrothiazol-2-ylidene -   tzn: tetrahydro-1,3-thiazin-2-ylidene

In the Tables, “di” indicates that there are two identical substituents, and “tri” indicates that there are three identical substituents.

The binding position of rings 1 to 21 with ring B is the position indicated by a black dot, which is located at the right end of the aforementioned chemical structure.

The substituents represented by the abbreviations as X and Y in Table 1, are shown below.

TABLE 1

Compound No. X, Y R³ 1-1 O═ Ph 1-2 S═ Ph 1-3 cPr Ph 1-4 cBu Ph 1-5 cPent Ph 1-6 cHex Ph 1-7 cHept Ph 1-8 oxi Ph 1-9 oxe Ph 1-10 oxo Ph 1-11 oxa Ph 1-12 dioxo Ph 1-13 dioxa Ph 1-14 dioxe Ph 1-15 dithio Ph 1-16 dithia Ph 1-17 ring 1 Ph 1-18 ring 2 Ph 1-19 oxathio Ph 1-20 oxathia Ph 1-21 ozl Ph 1-22 ozn Ph 1-23 tzl Ph 1-24 tzn Ph 1-25 3-HM-cPent Ph 1-26 4-HM-dioxo Ph 1-27 4-HM-dithio Ph 1-28 4-HM-oxathio Ph 1-29 3,4-diHM-cPent Ph 1-30 4,5-diHM-dioxo Ph 1-31 4,5-diHM-dithio Ph 1-32 4,5-diHM-oxathio Ph 1-33 3,4-diHE-cPent Ph 1-34 4,5-diHE-dioxo Ph 1-35 4,5-diHE-dithio Ph 1-36 4,5-diHE-oxathio Ph 1-37 3-HE-cPent Ph 1-38 4-HE-dioxo Ph 1-39 4-HE-dithio Ph 1-40 4-HE-oxathio Ph 1-41 3-HP-cPent Ph 1-42 4-HP-dioxo Ph 1-43 4-HP-dithio Ph 1-44 4-HP-oxathio Ph 1-45 3-HB-cPent Ph 1-46 4-HB-dioxo Ph 1-47 4-HB-dithio Ph 1-48 4-HB-oxathio Ph 1-49 ring 3 Ph 1-50 ring 4 Ph 1-51 ring 5 Ph 1-52 ring 6 Ph 1-53 ring 7 Ph 1-54 ring 8 Ph 1-55 ring 9 Ph 1-56 ring 10 Ph 1-57 3,4-diCH₂NHAc-cPent Ph 1-58 4,5-diCH₂NHAc-dioxo Ph 1-59 4,5-diCH₂NHAc-dithio Ph 1-60 4,5-diCH₂NHAc-oxathio Ph 1-61 ring 11 Ph 1-62 ring 12 Ph 1-63 ring 13 Ph 1-64 ring 14 Ph 1-65 4-OH-cHex Ph 1-66 5-OH-dioxa Ph 1-67 5-OH-dithia Ph 1-68 5-OH-oxathia Ph 1-69 4-NHAc-cHex Ph 1-70 5-NHAc-dioxa Ph 1-71 5-NHAc-dithia Ph 1-72 5-NHAc-oxathia Ph 1-73 4,4-diMe-cHex Ph 1-74 5,5-diMe-dioxa Ph 1-75 5,5-diMe-dithia Ph 1-76 5,5-diMe-oxathia Ph 1-77 4,4-diHM-cHex Ph 1-78 5,5-diHM-dioxa Ph 1-79 5,5-diHM-dithia Ph 1-80 5,5-diHM-oxathia Ph 1-81 ring 15 Ph 1-82 ring 16 Ph 1-83 ring 17 Ph 1-84 ring 18 Ph 1-85 4,4-diCO₂Et-cHex Ph 1-86 5,5-diCO₂Et-dioxa Ph 1-87 5,5-diCO₂Et-dithia Ph 1-88 5,5-diCO₂Et-oxathia h 1-89 O═ 4-F—Ph 1-90 S═ 4-F—Ph 1-91 cPr 4-F—Ph 1-92 cBu 4-F—Ph 1-93 cPent 4-F—Ph 1-94 cHex 4-F—Ph 1-95 cHept 4-F—Ph 1-96 oxi 4-F—Ph 1-97 oxe 4-F—Ph 1-98 oxo 4-F—Ph 1-99 oxa 4-F—Ph 1-100 dioxo 4-F—Ph 1-101 dioxa 4-F—Ph 1-102 dioxe 4-F—Ph 1-103 dithio 4-F—Ph 1-104 dithia 4-F—Ph 1-105 ring 1 4-F—Ph 1-106 ring 2 4-F—Ph 1-107 oxathio 4-F—Ph 1-108 oxathia 4-F—Ph 1-109 ozl 4-F—Ph 1-110 ozn 4-F—Ph 1-111 tzl 4-F—Ph 1-112 tzn 4-F—Ph 1-113 3-HM-cPent 4-F—Ph 1-114 4-HM-dioxo 4-F—Ph 1-115 4-HM-dithio 4-F—Ph 1-116 4-HM-oxathio 4-F—Ph 1-117 3,4-diHM-cPent 4-F—Ph 1-118 4,5-diHM-dioxo 4-F—Ph 1-119 4,5-diHM-dithio 4-F—Ph 1-120 4,5-diHM-oxathio 4-F—Ph 1-121 3,4-diHE-cPent 4-F—Ph 1-122 4,5-diHE-diaxo 4-F—Ph 1-123 4,5-diHE-dithio 4-F—Ph 1-124 4,5-diHE-oxathio 4-F—Ph 1-125 3-HE-cPent 4-F—Ph 1-126 4-HE-dioxo 4-F—Ph 1-127 4-HE-dithio 4-F—Ph 1-128 4-HE-oxathio 4-F—Ph 1-129 3-HP-cPent 4-F—Ph 1-130 4-HP-dioxo 4-F—Ph 1-131 4-HP-dithio 4-F—Ph 1-132 4-HP-oxathio 4-F—Ph 1-133 3-HB-cPent 4-F—Ph 1-134 4-HB-dioxo 4-F—Ph 1-135 4-HB-dithio 4-F—Ph 1-136 4-HB-oxathio 4-F—Ph 1-137 ring 3 4-F—Ph 1-138 ring 4 4-F—Ph 1-139 ring 5 4-F—Ph 1-140 ring 6 4-F—Ph 1-141 ring 7 4-F—Ph 1-142 ring 8 4-F—Ph 1-143 ring 9 4-F—Ph 1-144 ring 10 4-F—Ph 1-145 3,4-diCH₂NHAc-cPent 4-F—Ph 1-146 4,5-diCH₂NHAc-dioxo 4-F—Ph 1-147 4,5-diCH₂NHAc-dithio 4-F—Ph 1-148 4,5-diCH₂NHAc-oxathio 4-F—Ph 1-149 ring 11 4-F—Ph 1-150 ring 12 4-F—Ph 1-151 ring 13 4-F—Ph 1-152 ring 14 4-F—Ph 1-153 4-OH-cHex 4-F—Ph 1-154 5-OH-dioxa 4-F—Ph 1-155 5-OH-dithia 4-F—Ph 1-156 5-OH-oxathia 4-F—Ph 1-157 4-NHAc-cHex 4-F—Ph 1-158 5-NHAc-dioxa 4-F—Ph 1-159 5-NHAc-dithia 4-F—Ph 1-160 5-NHAc-oxathia 4-F—Ph 1-161 4,4-diMe-cHex 4-F—Ph 1-162 5,5-diMe-dioxa 4-F—Ph 1-163 5,5-diMe-dithia 4-F—Ph 1-164 5,5-diMe-oxathia 4-F—Ph 1-165 4,4-diHM-cHex 4-F—Ph 1-166 5,5-diHM-dioxa 4-F—Ph 1-167 5,5-diHM-dithia 4-F—Ph 1-168 5,5-diHM-oxathia 4-F—Ph 1-169 ring 15 4-F—Ph 1-170 ring 16 4-F—Ph 1-171 ring 17 4-F—Ph 1-172 ring 18 4-F—Ph 1-173 4,4-diCO₂Et-cHex 4-F—Ph 1-174 5,5-diCO₂Et-dioxa 4-F—Ph 1-175 5,5-diCO₂Et-dithia 4-F—Ph 1-176 5,5-diCO₂Et-oxathia 4-F—Ph 1-177 O═ 2-Cl—Ph 1-178 S═ 2-Cl—Ph 1-179 cPr 2-Cl—Ph 1-180 cBn 2-Cl—Ph 1-181 cPent 2-Cl—Ph 1-182 cHex 2-Cl—Ph 1-183 cHept 2-Cl—Ph 1-184 oxi 2-Cl—Ph 1-185 oxe 2-Cl—Ph 1-186 oxo 2-Cl—Ph 1-187 oxa 2-Cl—Ph 1-188 dioxo 2-Cl—Ph 1-189 dioxa 2-Cl—Ph 1-190 dioxe 2-Cl—Ph 1-191 dithio 2-Cl—Ph 1-192 dithia 2-Cl—Ph 1-193 ring 1 2-Cl—Ph 1-194 ring 2 2-Cl—Ph 1-195 oxathio 2-Cl—Ph 1-196 oxathia 2-Cl—Ph 1-197 ozl 2-Cl—Ph 1-198 ozn 2-Cl—Ph 1-199 tzl 2-Cl—Ph 1-200 tzn 2-Cl—Ph 1-201 3-HM-cPent 2-Cl—Ph 1-202 4-HM-dioxo 2-Cl—Ph 1-203 4-HM-dithio 2-Cl—Ph 1-204 4-HM-oxathio 2-Cl—Ph 1-205 3,4-diHM-cPent 2-Cl—Ph 1-206 4,5-diHM-dioxo 2-Cl—Ph 1-207 4,5-diHM-dithio 2-Cl—Ph 1-208 4,5-diHM-oxathio 2-Cl—Ph 1-209 3,4-diHE-cPent 2-Cl—Ph 1-210 4,5-diHE-dioxo 2-Cl—Ph 1-211 4,5-diHE-dithio 2-Cl—Ph 1-212 4,5-diHE-oxathio 2-Cl—Ph 1-213 3-HE-cPent 2-Cl—Ph 1-214 4-HE-dioxo 2-Cl—Ph 1-215 4-HE-dithio 2-Cl—Ph 1-216 4-HE-oxathio 2-Cl—Ph 1-217 3-HP-cPent 2-Cl—Ph 1-218 4-HP-dioxo 2-Cl—Ph 1-219 4-HP-dithio 2-Cl—Ph 1-220 4-HP-oxathio 2-Cl—Ph 1-221 3-HB-cPent 2-Cl—Ph 1-222 4-HB-dioxo 2-Cl—Ph 1-223 4-HB-dithio 2-Cl—Ph 1-224 4-HB-oxathio 2-Cl—Ph 1-225 ring 3 2-Cl—Ph 1-226 ring 4 2-Cl—Ph 1-227 ring 5 2-Cl—Ph 1-228 ring 6 2-Cl—Ph 1-229 ring 7 2-Cl—Ph 1-230 ring 8 2-Cl—Ph 1-231 ring 9 2-Cl—Ph 1-232 ring 10 2-Cl—Ph 1-233 3,4-diCH₂NHAc-cPent 2-Cl—Ph 1-234 4,5-diCH₂NHAc-dioxo 2-Cl—Ph 1-235 4,5-diCH₂NHAc-dithio 2-Cl—Ph 1-236 4,5-diCH₂NHAc-oxathio 2-Cl—Ph 1-237 ring 11 2-Cl—Ph 1-238 ring 12 2-Cl—Ph 1-239 ring 13 2-Cl—Ph 1-240 ring 14 2-Cl—Ph 1-241 4-OH-cHex 2-Cl—Ph 1-242 5-OH-dioxa 2-Cl—Ph 1-243 5-OH-dithia 2-Cl—Ph 1-244 5-OH-oxathia 2-Cl—Ph 1-245 4-NHAc-cHex 2-Cl—Ph 1-246 5-NHAc-dioxa 2-Cl—Ph 1-247 5-NHAc-dithia 2-Cl—Ph 1-248 5-NHAc-oxathia 2-Cl—Ph 1-249 4,4-diMe-cHex 2-Cl—Ph 1-250 5,5-diMe-dioxa 2-Cl—Ph 1-251 5,5-diMe-dithia 2-Cl—Ph 1-252 5,5-diMe-oxathia 2-Cl—Ph 1-253 4,4-diHM-cHex 2-Cl—Ph 1-254 5,5-diHM-dioxa 2-Cl—Ph 1-255 5,5-diHM-dithia 2-Cl—Ph 1-256 5,5-diHM-oxathia 2-Cl—Ph 1-257 ring 15 2-Cl—Ph 1-258 ring 16 2-Cl—Ph 1-259 ring 17 2-Cl—Ph 1-260 ring 18 2-Cl—Ph 1-261 4,4-diCO₂Et-cHex 2-Cl—Ph 1-262 5,5-diCO₂Et-dioxa 2-Cl—Ph 1-263 5,5-diCO₂Et-dithia 2-Cl—Ph 1-264 5,5-diCO₂Et-oxathia 2-Cl—Ph 1-265 O═ 2,4-diF—Ph 1-266 S═ 2,4-diF—Ph 1-267 cPr 2,4-diF—Ph 1-268 cBu 2,4-diF—Ph 1-269 cPent 2,4-diF—Ph 1-270 cHex 2,4-diF—Ph 1-271 cHept 2,4-diF—Ph 1-272 oxi 2,4-diF—Ph 1-273 oxe 2,4-diF—Ph 1-274 oxo 2,4-diF—Ph 1-275 oxa 2,4-diF—Ph 1-276 dioxo 2,4-diF—Ph 1-277 dioxa 2,4-diF—Ph 1-278 dioxe 2,4-diF—Ph 1-279 dithio 2,4-diF—Ph 1-280 dithia 2,4-diF—Ph 1-281 ring 1 2,4-diF—Ph 1-282 ring 2 2,4-diF—Ph 1-283 oxathio 2,4-diF—Ph 1-284 oxathia 2,4-diF—Ph 1-285 ozl 2,4-diF—Ph 1-286 ozn 2,4-diF—Ph 1-287 tzl 2,4-diF—Ph 1-288 tzn 2,4-diF—Ph 1-289 3-HM-cPent 2,4-diF—Ph 1-290 4-HM-dioxo 2,4-diF—Ph 1-291 4-HM-dithio 2,4-diF—Ph 1-292 4-HM-oxathio 2,4-diF—Ph 1-293 3,4-diHM-cPent 2,4-diF—Ph 1-294 4,5-diHM-dioxo 2,4-diF—Ph 1-295 4,5-diHM-dithio 2,4-diF—Ph 1-296 4,5-diHM-oxathio 2,4-diF—Ph 1-297 3,4-diHE-cPent 2,4-diF—Ph 1-298 4,5-diHE-dioxo 2,4-diF—Ph 1-299 4,5-diHE-dithio 2,4-diF—Ph 1-300 4,5-diHE-oxathio 2,4-diF—Ph 1-301 3-HE-cPent 2,4-diF—Ph 1-302 4-HE-dioxo 2,4-diF—Ph 1-303 4-HE-dithio 2,4-diF—Ph 1-304 4-HE-oxathio 2,4-diF—Ph 1-305 3-HP-cPent 2,4-diF—Ph 1-306 4-HP-dioxo 2,4-diF—Ph 1-307 4-HP-dithio 2,4-diF—Ph 1-308 4-HP-oxathio 2,4-diF—Ph 1-309 3-HB-cPent 2,4-diF—Ph 1-310 4-HB-dioxo 2,4-diF—Ph 1-311 4-HB-dithio 2,4-diF—Ph 1-312 4-HB-oxathio 2,4-diF—Ph 1-313 ring 3 2,4-diF—Ph 1-314 ring 4 2,4-diF—Ph 1-315 ring 5 2,4-diF—Ph 1-316 ring 6 2,4-diF—Ph 1-317 ring 7 2,4-diF—Ph 1-318 ring 8 2,4-diF—Ph 1-319 ring 9 2,4-diF—Ph 1-320 ring 10 2,4-diF—Ph 1-321 3,4-diCH₂NHAc-cPent 2,4-diF—Ph 1-322 4,5-diCH₂NHAc-dioxo 2,4-diF—Ph 1-323 4,5-diCH₂NHAc-dithio 2,4-diF—Ph 1-324 4,5-diCH₂NHAc-oxathio 2,4-diF—Ph 1-325 ring 11 2,4-diF—Ph 1-326 ring 12 2,4-diF—Ph 1-327 ring 13 2,4-diF—Ph 1-328 ring 14 2,4-diF—Ph 1-329 4-OH-cHex 2,4-diF—Ph 1-330 5-OH-dioxa 2,4-diF—Ph 1-331 5-OH-dithia 2,4-diF—Ph 1-332 5-OH-oxathia 2,4-diF—Ph 1-333 4-NHAc-cHex 2,4-diF—Ph 1-334 5-NHAc-dioxa 2,4-diF—Ph 1-335 5-NHAc-dithia 2,4-diF—Ph 1-336 5-NHAc-oxathia 2,4-diF—Ph 1-337 4,4-diMe-cHex 2,4-diF—Ph 1-338 5,5-diMe-dioxa 2,4-diF—Ph 1-339 5,5-diMe-dithia 2,4-diF—Ph 1-340 5,5-diMe-oxathia 2,4-diF—Ph 1-341 4,4-diHM-cHex 2,4-diF—Ph 1-342 5,5-diHM-dioxa 2,4-diF—Ph 1-343 5,5-diHM-dithia 2,4-diF—Ph 1-344 5,5-diHM-oxathia 2,4-diF—Ph 1-345 ring 15 2,4-diF—Ph 1-346 ring 16 2,4-diF—Ph 1-347 ring 17 2,4-diF—Ph 1-348 ring 18 2,4-diF—Ph 1-349 4,4-diCO₂Et-cHex 2,4-diF—Ph 1-350 5,5-diCO₂Et-dioxa 2,4-diF—Ph 1-351 5,5-diCO₂Et-dithia 2,4-diF—Ph 1-352 5,5-diCO₂Et-oxathia 2,4-diF—Ph 1-353 O═ 2-Cl-4-F—Ph 1-354 S═ 2-Cl-4-F—Ph 1-355 cPr 2-Cl-4-F—Ph 1-356 cBu 2-Cl-4-F—Ph 1-357 cPent 2-Cl-4-F—Ph 1-358 cHex 2-Cl-4-F—Ph 1-359 cHept 2-Cl-4-F—Ph 1-360 oxi 2-Cl-4-F—Ph 1-361 oxe 2-Cl-4-F—Ph 1-362 oxo 2-Cl-4-F—Ph 1-363 oxa 2-Cl-4-F—Ph 1-364 dioxo 2-Cl-4-F—Ph 1-365 dioxa 2-Cl-4-F—Ph 1-366 dioxe 2-Cl-4-F—Ph 1-367 dithio 2-Cl-4-F—Ph 1-368 dithia 2-Cl-4-F—Ph 1-369 ring 1 2-Cl-4-F—Ph 1-370 ring 2 2-Cl-4-F—Ph 1-371 oxathio 2-Cl-4-F—Ph 1-372 oxathia 2-Cl-4-F—Ph 1-373 ozl 2-Cl-4-F—Ph 1-374 ozn 2-Cl-4-F—Ph 1-375 tzl 2-Cl-4-F—Ph 1-376 tzn 2-Cl-4-F—Ph 1-377 3-HM-cPent 2-Cl-4-F—Ph 1-378 4-HM-dioxo 2-Cl-4-F—Ph 1-379 4-HM-dithio 2-Cl-4-F—Ph 1-380 4-HM-oxathio 2-Cl-4-F—Ph 1-381 3,4-diHM-cPent 2-Cl-4-F—Ph 1-382 4,5-diHM-dioxo 2-Cl-4-F—Ph 1-383 4,5-diHM-dithio 2-Cl-4-F—Ph 1-384 4,5-diHM-oxathio 2-Cl-4-F—Ph 1-385 3,4-diHE-cPent 2-Cl-4-F—Ph 1-386 4,5-diHE-dioxo 2-Cl-4-F—Ph 1-387 4,5-diHE-dithio 2-Cl-4-F—Ph 1-388 4,5-diHE-oxathio 2-Cl-4-F—Ph 1-389 3-HE-cPent 2-Cl-4-F—Ph 1-390 4-HE-dioxo 2-Cl-4-F—Ph 1-391 4-HE-dithio 2-Cl-4-F—Ph 1-392 4-HE-oxathio 2-Cl-4-F—Ph 1-393 3-HP-cPent 2-Cl-4-F—Ph 1-394 4-HP-dioxo 2-Cl-4-F—Ph 1-395 4-HP-dithio 2-Cl-4-F—Ph 1-396 4-HP-oxathio 2-Cl-4-F—Ph 1-397 3-HB-cPent 2-Cl-4-F—Ph 1-398 4-HB-dioxo 2-Cl-4-F—Ph 1-399 4-HB-dithio 2-Cl-4-F—Ph 1-400 4-HB-oxathio 2-Cl-4-F—Ph 1-401 ring 3 2-Cl-4-F—Ph 1-402 ring 4 2-Cl-4-F—Ph 1-403 ring 5 2-Cl-4-F—Ph 1-404 ring 6 2-Cl-4-F—Ph 1-405 ring 7 2-Cl-4-F—Ph 1-406 ring 8 2-Cl-4-F—Ph 1-407 ring 9 2-Cl-4-F—Ph 1-408 ring 10 2-Cl-4-F—Ph 1-409 3,4-diCH₂NHAc-cPent 2-Cl-4-F—Ph 1-410 4,5-diCH₂NHAc-dioxo 2-Cl-4-F—Ph 1-411 4,5-diCH₂NHAc-dithio 2-Cl-4-F—Ph 1-412 4,5-diCH₂NHAc-oxathio 2-Cl-4-F—Ph 1-413 ring 11 2-Cl-4-F—Ph 1-414 ring 12 2-Cl-4-F—Ph 1-415 ring 13 2-Cl-4-F—Ph 1-416 ring 14 2-Cl-4-F—Ph 1-417 4-OH-cHex 2-Cl-4-F—Ph 1-418 5-OH-dioxa 2-Cl-4-F—Ph 1-419 5-OH-dithia 2-Cl-4-F—Ph 1-420 5-OH-oxathia 2-Cl-4-F—Ph 1-421 4-NHAc-cHex 2-Cl-4-F—Ph 1-422 5-NHAc-dioxa 2-Cl-4-F—Ph 1-423 5-NHAc-dithia 2-Cl-4-F—Ph 1-424 5-NHAc-oxathia 2-Cl-4-F—Ph 1-425 4,4-diMe-cHex 2-Cl-4-F—Ph 1-426 5,5-diMe-dioxa 2-Cl-4-F—Ph 1-427 5,5-diMe-dithia 2-Cl-4-F—Ph 1-428 5,5-diMe-oxathia 2-Cl-4-F—Ph 1-429 4,4-diHM-cHex 2-Cl-4-F—Ph 1-430 5,5-diHM-dioxa 2-Cl-4-F—Ph 1-431 5,5-diHM-dithia 2-Cl-4-F—Ph 1-432 5,5-diHM-oxathia 2-Cl-4-F—Ph 1-433 ring 15 2-Cl-4-F—Ph 1-434 ring 16 2-Cl-4-F—Ph 1-435 ring 17 2-Cl-4-F—Ph 1-436 ring 18 2-Cl-4-F—Ph 1-437 4,4-diCO₂Et-cHex 2-Cl-4-F—Ph 1-438 5,5-diCO₂Et-dioxa 2-Cl-4-F—Ph 1-439 5,5-diCO₂Et-dithia 2-Cl-4-F—Ph 1-440 5,5-diCO₂Et-oxathia 2-Cl-4-F—Ph 1-441 O═ 2-Cl-4-Me—Ph 1-442 S═ 2-Cl-4-Me—Ph 1-443 cPr 2-Cl-4-Me—Ph 1-444 cBu 2-Cl-4-Me—Ph 1-445 cPent 2-Cl-4-Me—Ph 1-446 cHex 2-Cl-4-Me—Ph 1-447 cHept 2-Cl-4-Me—Ph 1-448 oxi 2-Cl-4-Me—Ph 1-449 oxe 2-Cl-4-Me—Ph 1-450 oxo 2-Cl-4-Me—Ph 1-451 oxa 2-Cl-4-Me—Ph 1-452 dioxo 2-Cl-4-Me—Ph 1-453 dioxa 2-Cl-4-Me—Ph 1-454 dioxe 2-Cl-4-Me—Ph 1-455 dithio 2-Cl-4-Me—Ph 1-456 dithia 2-Cl-4-Me—Ph 1-457 ring 1 2-Cl-4-Me—Ph 1-458 ring 2 2-Cl-4-Me—Ph 1-459 oxathio 2-Cl-4-Me—Ph 1-460 oxathia 2-Cl-4-Me—Ph 1-461 ozl 2-Cl-4-Me—Ph 1-462 ozn 2-Cl-4-Me—Ph 1-463 tzl 2-Cl-4-Me—Ph 1-464 tzn 2-Cl-4-Me—Ph 1-465 3-HM-cPent 2-Cl-4-Me—Ph 1-466 4-HM-dioxo 2-Cl-4-Me—Ph 1-467 4-HM-dithio 2-Cl-4-Me—Ph 1-468 4-HM-oxathio 2-Cl-4-Me—Ph 1-469 3,4-diHM-cPent 2-Cl-4-Me—Ph 1-470 4,5-diHM-dioxo 2-Cl-4-Me—Ph 1-471 4,5-diHM-dithio 2-Cl-4-Me—Ph 1-472 4,5-diHM-oxathio 2-Cl-4-Me—Ph 1-473 3,4-diHE-cPent 2-Cl-4-Me—Ph 1-474 4,5-diHE-dioxo 2-Cl-4-Me—Ph 1-475 4,5-diHE-dithio 2-Cl-4-Me—Ph 1-476 4,5-diHE-oxathio 2-Cl-4-Me—Ph 1-477 3-HE-cPent 2-Cl-4-Me—Ph 1-478 4-HE-dioxo 2-Cl-4-Me—Ph 1-479 4-HE-dithio 2-Cl-4-Me—Ph 1-480 4-HE-oxathio 2-Cl-4-Me—Ph 1-481 3-HP-cPent 2-Cl-4-Me—Ph 1-482 4-HP-dioxo 2-Cl-4-Me—Ph 1-483 4-HP-dithio 2-Cl-4-Me—Ph 1-484 4-HP-oxathio 2-Cl-4-Me—Ph 1-485 3-HB-cPent 2-Cl-4-Me—Ph 1-486 4-HB-dioxo 2-Cl-4-Me—Ph 1-487 4-HB-dithio 2-Cl-4-Me—Ph 1-488 4-HB-oxathio 2-Cl-4-Me—Ph 1-489 ring 3 2-Cl-4-Me—Ph 1-490 ring 4 2-Cl-4-Me—Ph 1-491 ring 5 2-Cl-4-Me—Ph 1-492 ring 6 2-Cl-4-Me—Ph 1-493 ring 7 2-Cl-4-Me—Ph 1-494 ring 8 2-Cl-4-Me—Ph 1-495 ring 9 2-Cl-4-Me—Ph 1-496 ring 10 2-Cl-4-Me—Ph 1-497 3,4-diCH₂NHAc-cPent 2-Cl-4-Me—Ph 1-498 4,5-diCH₂NHAc-dioxo 2-Cl-4-Me—Ph 1-499 4,5-diCH₂NHAc-dithio 2-Cl-4-Me—Ph 1-500 4,5-diCH₂NHAc-oxathio 2-Cl-4-Me—Ph 1-501 ring 11 2-Cl-4-Me—Ph 1-502 ring 12 2-Cl-4-Me—Ph 1-503 ring 13 2-Cl-4-Me—Ph 1-504 ring 14 2-Cl-4-Me—Ph 1-505 4-OH-cHex 2-Cl-4-Me—Ph 1-506 5-OH-dioxa 2-Cl-4-Me—Ph 1-507 5-OH-dithia 2-Cl-4-Me—Ph 1-508 5-OH-oxathia 2-Cl-4-Me—Ph 1-509 4-NHAc-cHex 2-Cl-4-Me—Ph 1-510 5-NHAc-dioxa 2-Cl-4-Me—Ph 1-511 5-NHAc-dithia 2-Cl-4-Me—Ph 1-512 5-NHAc-oxathia 2-Cl-4-Me—Ph 1-513 4,4-diMe-cHex 2-Cl-4-Me—Ph 1-514 5,5-diMe-dioxa 2-Cl-4-Me—Ph 1-515 5,5-diMe-dithia 2-Cl-4-Me—Ph 1-516 5,5-diMe-oxathia 2-Cl-4-Me—Ph 1-517 4,4-diHM-cHex 2-Cl-4-Me—Ph 1-518 5,5-diHM-dioxa 2-Cl-4-Me—Ph 1-519 5,5-diHM-dithia 2-Cl-4-Me—Ph 1-520 5,5-diHM-oxathia 2-Cl-4-Me—Ph 1-521 ring 15 2-Cl-4-Me—Ph 1-522 ring 16 2-Cl-4-Me—Ph 1-523 ring 17 2-Cl-4-Me—Ph 1-524 ring 18 2-Cl-4-Me—Ph 1-525 4,4-diCO₂Et-cHex 2-Cl-4-Me—Ph 1-526 5,5-diCO₂Et-dioxa 2-Cl-4-Me—Ph 1-527 5,5-diCO₂Et-dithia 2-Cl-4-Me—Ph 1-528 5,5-diCO₂Et-oxathia 2-Cl-4-Me—Ph 1-529 O═ 2-nBu—Ph 1-530 S═ 2-nBu—Ph 1-531 cPr 2-nBu—Ph 1-532 cBu 2-nBu—Ph 1-533 cPent 2-nBu—Ph 1-534 cHex 2-nBu—Ph 1-535 cHept 2-nBu—Ph 1-536 oxi 2-nBu—Ph 1-537 oxe 2-nBu—Ph 1-538 oxo 2-nBu—Ph 1-539 oxa 2-nBu—Ph 1-540 dioxo 2-nBu—Ph 1-541 dioxa 2-nBu—Ph 1-542 dioxe 2-nBu—Ph 1-543 dithio 2-nBu—Ph 1-544 dithia 2-nBu—Ph 1-545 ring 1 2-nBu—Ph 1-546 ring 2 2-nBu—Ph 1-547 oxathio 2-nBu—Ph 1-548 oxathia 2-nBu—Ph 1-549 ozl 2-nBu—Ph 1-550 ozn 2-nBu—Ph 1-551 tzl 2-nBu—Ph 1-552 tzn 2-nBu—Ph 1-553 3-HM-cPent 2-nBu—Ph 1-554 4-HM-dioxo 2-nBu—Ph 1-555 4-HM-dithio 2-nBu—Ph 1-556 4-HM-oxathio 2-nBu—Ph 1-557 3,4-diHM-cPent 2-nBu—Ph 1-558 4,5-diHM-dioxo 2-nBu—Ph 1-559 4,5-diHM-dithio 2-nBu—Ph 1-560 4,5-diHM-oxathio 2-nBu—Ph 1-561 3,4-diHE-cPent 2-nBu—Ph 1-562 4,5-diHE-dioxo 2-nBu—Ph 1-563 4,5-diHE-dithio 2-nBu—Ph 1-564 4,5-diHE-oxathio 2-nBu—Ph 1-565 3-HE-cPent 2-nBu—Ph 1-566 4-HE-dioxo 2-nBu—Ph 1-567 4-HE-dithio 2-nBu—Ph 1-568 4-HE-oxathio 2-nBu—Ph 1-569 3-HP-cPent 2-nBu—Ph 1-570 4-HP-dioxo 2-nBu—Ph 1-571 4-HP-dithio 2-nBu—Ph 1-572 4-HP-oxathio 2-nBu—Ph 1-573 3-HB-cPent 2-nBu—Ph 1-574 4-HB-dioxo 2-nBu—Ph 1-575 4-HB-dithio 2-nBu—Ph 1-576 4-HB-oxathio 2-nBu—Ph 1-577 ring 3 2-nBu—Ph 1-578 ring 4 2-nBu—Ph 1-579 ring 5 2-nBu—Ph 1-580 ring 6 2-nBu—Ph 1-581 ring 7 2-nBu—Ph 1-582 ring 8 2-nBu—Ph 1-583 ring 9 2-nBu—Ph 1-584 ring 10 2-nBu—Ph 1-585 3,4-diCH₂NHAc-cPent 2-nBu—Ph 1-586 4,5-diCH₂NHAc-dioxo 2-nBu—Ph 1-587 4,5-diCH₂NHAc-dithio 2-nBu—Ph 1-588 4,5-diCH₂NHAc-oxathio 2-nBu—Ph 1-589 ring 11 2-nBu—Ph 1-590 ring 12 2-nBu—Ph 1-591 ring 13 2-nBu—Ph 1-592 ring 14 2-nBu—Ph 1-593 4-OH-cHex 2-nBu—Ph 1-594 5-OH-dioxa 2-nBu—Ph 1-595 5-OH-dithia 2-nBu—Ph 1-596 5-OH-oxathia 2-nBu—Ph 1-597 4-NHAc-cHex 2-nBu—Ph 1-598 5-NHAc-dioxa 2-nBu—Ph 1-599 5-NHAc-dithia 2-nBu—Ph 1-600 5-NHAc-oxathia 2-nBu—Ph 1-601 4,4-diMe-cHex 2-nBu—Ph 1-602 5,5-diMe-dioxa 2-nBu—Ph 1-603 5,5-diMe-dithia 2-nBu—Ph 1-604 5,5-diMe-oxathia 2-nBu—Ph 1-605 4,4-diHM-cHex 2-nBu—Ph 1-606 5,5-diHM-dioxa 2-nBu—Ph 1-607 5,5-diHM-dithia 2-nBu—Ph 1-608 5,5-diHM-oxathia 2-nBu—Ph 1-609 ring 15 2-nBu—Ph 1-610 ring 16 2-nBu—Ph 1-611 ring 17 2-nBu—Ph 1-612 ring 18 2-nBu—Ph 1-612 4,4-diCO₂Et-cHex 2-nBu—Ph 1-614 5,5-diCO₂Et-dioxa 2-nBu—Ph 1-615 5,5-diCO₂Et-dithia 2-nBu—Ph 1-616 5,5-diCO₂Et-oxathia 2-nBu—Ph 1-617 O═ 2-nBu-4-F—Ph 1-618 S═ 2-nBu-4-F—Ph 1-619 cPr 2-nBu-4-F—Ph 1-620 cBu 2-nBu-4-F—Ph 1-621 cPent 2-nBu-4-F—Ph 1-622 cHex 2-nBu-4-F—Ph 1-623 cHept 2-nBu-4-F—Ph 1-624 oxi 2-nBu-4-F—Ph 1-625 oxe 2-nBu-4-F—Ph 1-626 oxo 2-nBu-4-F—Ph 1-627 oxa 2-nBu-4-F—Ph 1-628 dioxo 2-nBu-4-F—Ph 1-629 dioxa 2-nBu-4-F—Ph 1-630 dioxe 2-nBu-4-F—Ph 1-631 dithio 2-nBu-4-F—Ph 1-632 dithia 2-nBu-4-F—Ph 1-633 ring 1 2-nBu-4-F—Ph 1-634 ring 2 2-nBu-4-F—Ph 1-635 oxathio 2-nBu-4-F—Ph 1-636 oxathia 2-nBu-4-F—Ph 1-637 ozl 2-nBu-4-F—Ph 1-638 ozn 2-nBu-4-F—Ph 1-639 tzl 2-nBu-4-F—Ph 1-640 tzn 2-nBu-4-F—Ph 1-641 3-HM-cPent 2-nBu-4-F—Ph 1-642 4-HM-dioxo 2-nBu-4-F—Ph 1-643 4-HM-dithio 2-nBu-4-F—Ph 1-644 4-HM-oxathio 2-nBu-4-F—Ph 1-645 3,4-diHM-cPent 2-nBu-4-F—Ph 1-646 4,5-diHM-dioxo 2-nBu-4-F—Ph 1-647 4,5-diHM-dithio 2-nBu-4-F—Ph 1-648 4,5-diHM-oxathio 2-nBu-4-F—Ph 1-649 3,4-diHE-cPent 2-nBu-4-F—Ph 1-650 4,5-diHE-dioxo 2-nBu-4-F—Ph 1-651 4,5-diHE-dithio 2-nBu-4-F—Ph 1-652 4,5-diHE-oxathio 2-nBu-4-F—Ph 1-653 3-HE-cPent 2-nBu-4-F—Ph 1-654 4-HE-dioxo 2-nBu-4-F—Ph 1-655 4-HE-dithio 2-nBu-4-F—Ph 1-656 4-HE-oxathio 2-nBu-4-F—Ph 1-657 3-HP-cPent 2-nBu-4-F—Ph 1-658 4-HP-dioxo 2-nBu-4-F—Ph 1-659 4-HP-dithio 2-nBu-4-F—Ph 1-660 4-HP-oxathio 2-nBu-4-F—Ph 1-661 3-HB-cPent 2-nBu-4-F—Ph 1-662 4-HB-dioxo 2-nBu-4-F—Ph 1-663 4-HB-dithio 2-nBu-4-F—Ph 1-664 4-HB-oxathio 2-nBu-4-F—Ph 1-665 ring 3 2-nBu-4-F—Ph 1-666 ring 4 2-nBu-4-F—Ph 1-667 ring 5 2-nBu-4-F—Ph 1-668 ring 6 2-nBu-4-F—Ph 1-669 ring 7 2-nBu-4-F—Ph 1-670 ring 8 2-nBu-4-F—Ph 1-671 ring 9 2-nBu-4-F—Ph 1-672 ring 10 2-nBu-4-F—Ph 1-673 3,4-diCH₂NHAc-cPent 2-nBu-4-F—Ph 1-674 4,5-diCH₂NHAc-dioxo 2-nBu-4-F—Ph 1-675 4,5-diCH₂NHAc-dithio 2-nBu-4-F—Ph 1-676 4,5-diCH₂NHAc-oxathio 2-nBu-4-F—Ph 1-677 ring 11 2-nBu-4-F—Ph 1-678 ring 12 2-nBu-4-F—Ph 1-679 ring 13 2-nBu-4-F—Ph 1-680 ring 14 2-nBu-4-F—Ph 1-681 4-OH-cHex 2-nBu-4-F—Ph 1-682 5-OH-dioxa 2-nBu-4-F—Ph 1-683 5-OH-dithia 2-nBu-4-F—Ph 1-684 5-OH-oxathia 2-nBu-4-F—Ph 1-685 4-NHAc-cHex 2-nBu-4-F—Ph 1-686 5-NHAc-dioxa 2-nBu-4-F—Ph 1-687 5-NHAc-dithia 2-nBu-4-F—Ph 1-688 5-NHAc-oxathia 2-nBu-4-F—Ph 1-689 4,4-diMe-cHex 2-nBu-4-F—Ph 1-690 5,5-diMe-dioxa 2-nBu-4-F—Ph 1-691 5,5-diMe-dithia 2-nBu-4-F—Ph 1-692 5,5-diMe-oxathia 2-nBu-4-F—Ph 1-693 4,4-diHM-cHex 2-nBu-4-F—Ph 1-694 5,5-diHM-dioxa 2-nBu-4-F—Ph 1-695 5,5-diHM-dithia 2-nBu-4-F—Ph 1-696 5,5-diHM-oxathia 2-nBu-4-F—Ph 1-697 ring 15 2-nBu-4-F—Ph 1-698 ring 16 2-nBu-4-F—Ph 1-699 ring 17 2-nBu-4-F—Ph 1-700 ring 18 2-nBu-4-F—Ph 1-701 4,4-diCO₂Et-cHex 2-nBu-4-F—Ph 1-702 5,5-diCO₂Et-dioxa 2-nBu-4-F—Ph 1-703 5,5-diCO₂Et-dithia 2-nBu-4-F—Ph 1-704 5,5-diCO₂Et-oxathia 2-nBu-4-F—Ph 1-705 O═ 2-nHex—Ph 1-706 S═ 2-nHex—Ph 1-707 cPr 2-nHex—Ph 1-708 cBu 2-nHex—Ph 1-709 cPent 2-nHex—Ph 1-710 cHex 2-nHex—Ph 1-711 cHept 2-nHex—Ph 1-712 oxi 2-nHex—Ph 1-713 oxe 2-nHex—Ph 1-714 oxo 2-nHex—Ph 1-715 oxa 2-nHex—Ph 1-716 dioxo 2-nHex—Ph 1-717 dioxa 2-nHex—Ph 1-718 dioxe 2-nHex—Ph 1-719 dithio 2-nHex—Ph 1-720 dithia 2-nHex—Ph 1-721 ring 1 2-nHex—Ph 1-722 ring 2 2-nHex—Ph 1-723 oxathio 2-nHex—Ph 1-724 oxathia 2-nHex—Ph 1-725 ozl 2-nHex—Ph 1-726 ozn 2-nHex—Ph 1-727 tzl 2-nHex—Ph 1-728 tzn 2-nHex—Ph 1-729 3-HM-cPent 2-nHex—Ph 1-730 4-HM-dioxo 2-nHex—Ph 1-731 4-HM-dithio 2-nHex—Ph 1-732 4-HM-oxathio 2-nHex—Ph 1-733 3,4-diHM-cPent 2-nHex—Ph 1-734 4,5-diHM-dioxo 2-nHex—Ph 1-735 4,5-diHM-dithio 2-nHex—Ph 1-736 4,5-diHM-oxathio 2-nHex—Ph 1-737 3,4-diHE-cPent 2-nHex—Ph 1-738 4,5-diHE-dioxo 2-nHex—Ph 1-739 4,5-diHE-dithio 2-nHex—Ph 1-740 4,5-diHE-oxathio 2-nHex—Ph 1-741 3-HE-cPent 2-nHex—Ph 1-742 4-HE-dioxo 2-nHex—Ph 1-743 4-HE-dithio 2-nHex—Ph 1-744 4-HE-oxathio 2-nHex—Ph 1-745 3-HP-cPent 2-nHex—Ph 1-746 4-HP-dioxo 2-nHex—Ph 1-747 4-HP-dithio 2-nHex—Ph 1-748 4-HP-oxathio 2-nHex—Ph 1-749 3-HB-cPent 2-nHex—Ph 1-750 4-HB-dioxo 2-nHex—Ph 1-751 4-HB-dithio 2-nHex—Ph 1-752 4-HB-oxathio 2-nHex—Ph 1-753 ring 3 2-nHex—Ph 1-754 ring 4 2-nHex—Ph 1-755 ring 5 2-nHex—Ph 1-756 ring 6 2-nHex—Ph 1-757 ring 7 2-nHex—Ph 1-758 ring 8 2-nHex—Ph 1-759 ring 9 2-nHex—Ph 1-760 ring 10 2-nHex—Ph 1-761 3,4-diCH₂NHAc-cPent 2-nHex—Ph 1-762 4,5-diCH₂NHAc-dioxo 2-nHex—Ph 1-763 4,5-diCH₂NHAc-dithio 2-nHex—Ph 1-764 4,5-diCH₂NHAc-oxathio 2-nHex—Ph 1-765 ring 11 2-nHex—Ph 1-766 ring 12 2-nHex—Ph 1-767 ring 13 2-nHex—Ph 1-768 ring 14 2-nHex—Ph 1-769 4-OH-cHex 2-nHex—Ph 1-770 5-OH-dioxa 2-nHex—Ph 1-771 5-OH-dithia 2-nHex—Ph 1-772 5-OH-oxathia 2-nHex—Ph 1-773 4-NHAc-cHex 2-nHex—Ph 1-774 5-NHAc-dioxa 2-nHex—Ph 1-775 5-NHAc-dithia 2-nHex—Ph 1-776 5-NHAc-oxathia 2-nHex—Ph 1-777 4,4-diMe-cHex 2-nHex—Ph 1-778 5,5-diMe-dioxa 2-nHex—Ph 1-779 5,5-diMe-dithia 2-nHex—Ph 1-780 5,5-diMe-oxathia 2-nHex—Ph 1-781 4,4-diHM-cHex 2-nHex—Ph 1-782 5,5-diHM-dioxa 2-nHex—Ph 1-783 5,5-diHM-dithia 2-nHex—Ph 1-784 5,5-diHM-oxathia 2-nHex—Ph 1-785 ring 15 2-nHex—Ph 1-786 ring 16 2-nHex—Ph 1-787 ring 17 2-nHex—Ph 1-788 ring 18 2-nHex—Ph 1-789 4,4-diCO₂Et-cHex 2-nHex—Ph 1-790 5,5-diCO₂Et-dioxa 2-nHex—Ph 1-791 5,5-diCO₂Et-dithia 2-nHex—Ph 1-792 5,5-diCO₂Et-oxathia 2-nHex—Ph 1-793 O═ 4-F-2-nHex—Ph 1-794 S═ 4-F-2-nHex—Ph 1-795 cPr 4-F-2-nHex—Ph 1-796 cBu 4-F-2-nHex—Ph 1-797 cPent 4-F-2-nHex—Ph 1-798 cHex 4-F-2-nHex—Ph 1-799 cHept 4-F-2-nHex—Ph 1-800 oxi 4-F-2-nHex—Ph 1-801 oxe 4-F-2-nHex—Ph 1-802 oxo 4-F-2-nHex—Ph 1-803 oxa 4-F-2-nHex—Ph 1-804 dioxo 4-F-2-nHex—Ph 1-805 dioxa 4-F-2-nHex—Ph 1-806 dioxe 4-F-2-nHex—Ph 1-807 dithio 4-F-2-nHex—Ph 1-808 dithia 4-F-2-nHex—Ph 1-809 ring 1 4-F-2-nHex—Ph 1-810 ring 2 4-F-2-nHex—Ph 1-811 oxathio 4-F-2-nHex—Ph 1-812 oxathia 4-F-2-nHex—Ph 1-813 ozl 4-F-2-nHex—Ph 1-814 ozn 4-F-2-nHex—Ph 1-815 tzl 4-F-2-nHex—Ph 1-816 tzn 4-F-2-nHex—Ph 1-817 3-HM-cPent 4-F-2-nHex—Ph 1-818 4-HM-dioxo 4-F-2-nHex—Ph 1-819 4-HM-dithio 4-F-2-nHex—Ph 1-820 4-HM-oxathio 4-F-2-nHex—Ph 1-821 3,4-diHM-cPent 4-F-2-nHex—Ph 1-822 4,5-diHM-dioxo 4-F-2-nHex—Ph 1-823 4,5-diHM-dithio 4-F-2-nHex—Ph 1-824 4,5-diHM-oxathio 4-F-2-nHex—Ph 1-825 3,4-diHE-cPent 4-F-2-nHex—Ph 1-826 4,5-diHE-dioxo 4-F-2-nHex—Ph 1-827 4,5-diHE-dithio 4-F-2-nHex—Ph 1-828 4,5-diHE-oxathio 4-F-2-nHex—Ph 1-829 3-HE-cPent 4-F-2-nHex—Ph 1-830 4-HE-dioxo 4-F-2-nHex—Ph 1-831 4-HE-dithio 4-F-2-nHex—Ph 1-832 4-HE-oxathio 4-F-2-nHex—Ph 1-833 3-HP-cPent 4-F-2-nHex—Ph 1-834 4-HP-dioxo 4-F-2-nHex—Ph 1-835 4-HP-dithio 4-F-2-nHex—Ph 1-836 4-HP-oxathio 4-F-2-nHex—Ph 1-837 3-HB-cPent 4-F-2-nHex—Ph 1-838 4-HB-dioxo 4-F-2-nHex—Ph 1-839 4-HB-dithio 4-F-2-nHex—Ph 1-840 4-HB-oxathio 4-F-2-nHex—Ph 1-841 ring 3 4-F-2-nHex—Ph 1-842 ring 4 4-F-2-nHex—Ph 1-843 ring 5 4-F-2-nHex—Ph 1-844 ring 6 4-F-2-nHex—Ph 1-845 ring 7 4-F-2-nHex—Ph 1-846 ring 8 4-F-2-nHex—Ph 1-847 ring 9 4-F-2-nHex—Ph 1-848 ring 10 4-F-2-nHex—Ph 1-849 3,4-diCH₂NHAc-cPent 4-F-2-nHex—Ph 1-850 4,5-diCH₂NHAc-dioxo 4-F-2-nHex—Ph 1-851 4,5-diCH₂NHAc-dithio 4-F-2-nHex—Ph 1-852 4,5-diCH₂NHAc-oxathio 4-F-2-nHex—Ph 1-853 ring 11 4-F-2-nHex—Ph 1-854 ring 12 4-F-2-nHex—Ph 1-855 ring 13 4-F-2-nHex—Ph 1-856 ring 14 4-F-2-nHex—Ph 1-857 4-OH-cHex 4-F-2-nHex—Ph 1-858 5-OH-dioxa 4-F-2-nHex—Ph 1-859 5-OH-dithia 4-F-2-nHex—Ph 1-860 5-OH-oxathia 4-F-2-nHex—Ph 1-851 4-NHAc-cHex 4-F-2-nHex—Ph 1-852 5-NHAc-dioxa 4-F-2-nHex—Ph 1-863 5-NHAc-dithia 4-F-2-nHex—Ph 1-854 5-NHAc-oxathia 4-F-2-nHex—Ph 1-865 4,4-diMe-cHex 4-F-2-nHex—Ph 1-866 5,5-diMe-dioxa 4-F-2-nHex—Ph 1-857 5,5-diMe-dithia 4-F-2-nHex—Ph 1-868 5,5-diMe-oxathia 4-F-2-nHex—Ph 1-869 4,4-diHM-cHex 4-F-2-nHex—Ph 1-870 5,5-diHM-dioxa 4-F-2-nHex—Ph 1-871 5,5-diHM-dithia 4-F-2-nHex—Ph 1-872 5,5-diHM-oxathia 4-F-2-nHex—Ph 1-873 ring 15 4-F-2-nHex—Ph 1-874 ring 16 4-F-2-nHex—Ph 1-875 ring 17 4-F-2-nHex—Ph 1-876 ring 18 4-F-2-nHex—Ph 1-877 4,4-diCO₂Et-cHex 4-F-2-nHex—Ph 1-878 5,5-diCO₂Et-dioxa 4-F-2-nHex—Ph 1-879 5,5-diCO₂Et-dithia 4-F-2-nHex—Ph 1-880 5,5-diCO₂Et-oxathia 4-F-2-nHex—Ph 1-881 O═ 2-nHept-Ph 1-882 S═ 2-nHept-Ph 1-883 cPr 2-nHept-Ph 1-884 cBu 2-nHept-Ph 1-885 cPent 2-nHept-Ph 1-886 cHex 2-nHept-Ph 1-887 cHept 2-nHept-Ph 1-888 oxi 2-nHept-Ph 1-889 oxe 2-nHept-Ph 1-890 oxo 2-nHept-Ph 1-891 oxa 2-nHept-Ph 1-892 dioxo 2-nHept-Ph 1-893 dioxa 2-nHept-Ph 1-894 dioxe 2-nHept-Ph 1-895 dithio 2-nHept-Ph 1-896 dithia 2-nHept-Ph 1-897 ring 1 2-nHept-Ph 1-898 ring 2 2-nHept-Ph 1-899 oxathio 2-nHept-Ph 1-900 oxathia 2-nHept-Ph 1-901 ozl 2-nHept-Ph 1-902 ozn 2-nHept-Ph 1-903 tzl 2-nHept-Ph 1-904 tzn 2-nHept-Ph 1-905 3-HM-cPent 2-nHept-Ph 1-906 4-HM-dioxo 2-nHept-Ph 1-907 4-HM-dithio 2-nHept-Ph 1-908 4-HM-oxathio 2-nHept-Ph 1-909 3,4-diHM-cPent 2-nHept-Ph 1-910 4,5-diHM-dioxo 2-nHept-Ph 1-911 4,5-diHM-dithio 2-nHept-Ph 1-912 4,5-diHM-oxathio 2-nHept-Ph 1-913 3,4-diHE-cPent 2-nHept-Ph 1-914 4,5-diHE-dioxo 2-nHept-Ph 1-915 4,5-diHE-dithio 2-nHept-Ph 1-916 4,5-diHE-oxathio 2-nHept-Ph 1-917 3-HE-cPent 2-nHept-Ph 1-918 4-HE-dioxo 2-nHept-Ph 1-919 4-HE-dithio 2-nHept-Ph 1-920 4-HE-oxathio 2-nHept-Ph 1-921 3-HP-cPent 2-nHept-Ph 1-922 4-HP-dioxo 2-nHept-Ph 1-923 4-HP-dithio 2-nHept-Ph 1-924 4-HP-oxathio 2-nHept-Ph 1-925 3-HB-oPent 2-nHept-Ph 1-926 4-HB-dioxo 2-nHept-Ph 1-927 4-HB-dithio 2-nHept-Ph 1-928 4-HB-oxathio 2-nHept-Ph 1-929 ring 3 2-nHept-Ph 1-930 ring 4 2-nHept-Ph 1-931 ring 5 2-nHept-Ph 1-932 ring 6 2-nHept-Ph 1-933 ring 7 2-nHept-Ph 1-934 ring 8 2-nHept-Ph 1-935 ring 9 2-nHept-Ph 1-936 ring 10 2-nHept-Ph 1-937 3,4-diCH₂NHAc-cPent 2-nHept-Ph 1-938 4,5-diCH₂NHAc-dioxo 2-nHept-Ph 1-939 4,5-diCH₂NHAc-dithio 2-nHept-Ph 1-940 4,5-diCH₂NHAc-oxathi 2-nHept-Ph 1-941 ring 11 2-nHept-Ph 1-942 ring 12 2-nHept-Ph 1-943 ring 13 2-nHept-Ph 1-944 ring 14 2-nHept-Ph 1-945 4-OH-cHex 2-nHept-Ph 1-946 5-OH-dioxa 2-nHept-Ph 1-947 5-OH-dithia 2-nHept-Ph 1-948 5-OH-oxathia 2-nHept-Ph 1-949 4-NHAc-cHex 2-nHept-Ph 1-950 5-NHAc-dioxa 2-nHept-Ph 1-951 5-NHAc-dithia 2-nHept-Ph 1-952 5-NHAc-oxathia 2-nHept-Ph 1-953 4,4-diMe-cHex 2-nHept-Ph 1-954 5,5-diMe-dioxa 2-nHept-Ph 1-955 5,5-diMe-dithia 2-nHept-Ph 1-956 5,5-diMe-oxathia 2-nHept-Ph 1-957 4,4-diHM-cHex 2-nHept-Ph 1-958 5,5-diHM-dioxa 2-nHept-Ph 1-959 5,5-diHM-dithia 2-nHept-Ph 1-960 5,5-diHM-oxathia 2-nHept-Ph 1-961 ring 15 2-nHept-Ph 1-962 ring 16 2-nHept-Ph 1-963 ring 17 2-nHept-Ph 1-964 ring 18 2-nHept-Ph 1-965 4,4-diCO₂Et-cHex 2-nHept-Ph 1-966 5,5-diCO₂Et-dioxa 2-nHept-Ph 1-967 5,5-diCO₂Et-dithia 2-nHept-Ph 1-968 5,5-diCO₂Et-oxathia 2-nHept-Ph 1-969 O═ 4-F-2-nHept-Ph 1-970 S═ 4-F-2-nHept-Ph 1-971 cPr 4-F-2-nHept-Ph 1-972 cBu 4-F-2-nHept-Ph 1-973 cPent 4-F-2-nHept-Ph 1-974 cHex 4-F-2-nHept-Ph 1-975 cHept 4-F-2-nHept-Ph 1-976 oxi 4-F-2-nHept-Ph 1-977 oxe 4-F-2-nHept-Ph 1-978 oxo 4-F-2-nHept-Ph 1-979 oxa 4-F-2-nHept-Ph 1-980 dioxo 4-F-2-nHept-Ph 1-981 dioxa 4-F-2-nHept-Ph 1-982 dioxe 4-F-2-nHept-Ph 1-983 dithio 4-F-2-nHept-Ph 1-984 dithia 4-F-2-nHept-Ph 1-985 ring 1 4-F-2-nHept-Ph 1-986 ring 2 4-F-2-nHept-Ph 1-987 oxathio 4-F-2-nHept-Ph 1-988 oxathia 4-F-2-nHept-Ph 1-989 ozl 4-F-2-nHept-Ph 1-990 ozn 4-F-2-nHept-Ph 1-991 tzl 4-F-2-nHept-Ph 1-992 tzn 4-F-2-nHept-Ph 1-993 3-HM-cPent 4-F-2-nHept-Ph 1-994 4-HM-dioxo 4-F-2-nHept-Ph 1-995 4-HM-dithio 4-F-2-nHept-Ph 1-996 4-HM-oxathio 4-F-2-nHept-Ph 1-997 3,4-diHM-cPent 4-F-2-nHept-Ph 1-998 4,5-diHM-dioxo 4-F-2-nHept-Ph 1-999 4,5-diHM-dithio 4-F-2-nHept-Ph 1-1000 4,5-diHM-oxathio 4-F-2-nHept-Ph 1-1001 3,4-diHE-cPent 4-F-2-nHept-Ph 1-1002 4,5-diHE-dioxo 4-F-2-nHept-Ph 1-1003 4,5-diHE-dithio 4-F-2-nHept-Ph 1-1004 4,5-diHE-oxathio 4-F-2-nHept-Ph 1-1005 3-HE-cPent 4-F-2-nHept-Ph 1-1006 4-HE-dioxo 4-F-2-nHept-Ph 1-1007 4-HE-dithio 4-F-2-nHept-Ph 1-1008 4-HE-oxathio 4-F-2-nHept-Ph 1-1009 3-HP-cPent 4-F-2-nHept-Ph 1-1010 4-HP-dioxo 4-F-2-nHept-Ph 1-1011 4-HP-dithio 4-F-2-nHept-Ph 1-1012 4-HP-oxathio 4-F-2-nHept-Ph 1-1013 3-HB-cPent 4-F-2-nHept-Ph 1-1014 4-HB-dioxo 4-F-2-nHept-Ph 1-1015 4-HB-dithio 4-F-2-nHept-Ph 1-1016 4-HB-oxathio 4-F-2-nHept-Ph 1-1017 ring 3 4-F-2-nHept-Ph 1-1018 ring 4 4-F-2-nHept-Ph 1-1019 ring 5 4-F-2-nHept-Ph 1-1020 ring 6 4-F-2-nHept-Ph 1-1021 ring 7 4-F-2-nHept-Ph 1-1022 ring 8 4-F-2-nHept-Ph 1-1023 ring 9 4-F-2-nHept-Ph 1-1024 ring 10 4-F-2-nHept-Ph 1-1025 3,4-diCH₂NHAc-cPent 4-F-2-nHept-Ph 1-1026 4,5-diCH₂NHAc-dioxo 4-F-2-nHept-Ph 1-1027 4,5-diCH₂NHAc-dithio 4-F-2-nHept-Ph 1-1028 4,5-diCH₂NHAc-oxathio 4-F-2-nHept-Ph 1-1029 ring 11 4-F-2-nHept-Ph 1-1030 ring 12 4-F-2-nHept-Ph 1-1031 ring 13 4-F-2-nHept-Ph 1-1032 ring 14 4-F-2-nHept-Ph 1-1033 4-OH-cHex 4-F-2-nHept-Ph 1-1034 5-OH-dioxa 4-F-2-nHept-Ph 1-1035 5-OH-dithia 4-F-2-nHept-Ph 1-1036 5-OH-oxathia 4-F-2-nHept-Ph 1-1037 4-NHAc-cHex 4-F-2-nHept-Ph 1-1038 5-NHAc-dioxa 4-F-2-nHept-Ph 1-1039 5-NHAc-dithia 4-F-2-nHept-Ph 1-1040 5-NHAc-oxathia 4-F-2-nHept-Ph 1-1041 4,4-diMe-cHex 4-F-2-nHept-Ph 1-1042 5,5-diMe-dioxa 4-F-2-nHept-Ph 1-1043 5,5-diMe-dithia 4-F-2-nHept-Ph 1-1044 5,5-diMe-oxathia 4-F-2-nHept-Ph 1-1045 4,4-diHM-cHex 4-F-2-nHept-Ph 1-1046 5,5-diHM-dioxa 4-F-2-nHept-Ph 1-1047 5,5-diHM-dithia 4-F-2-nHept-Ph 1-1048 5,5-diHM-oxathia 4-F-2-nHept-Ph 1-1049 ring 15 4-F-2-nHept-Ph 1-1050 ring 16 4-F-2-nHept-Ph 1-1051 ring 17 4-F-2-nHept-Ph 1-1052 ring 18 4-F-2-nHept-Ph 1-1053 4,4-diCO₂Et-cHex 4-F-2-nHept-Ph 1-1054 5,5-diCO₂Et-dioxa 4-F-2-nHept-Ph 1-1055 5,5-diCO₂Et-dithia 4-F-2-nHept-Ph 1-1056 5,5-diCO₂Et-oxathia 4-F-2-nHept-Ph 1-1057 H,H Pyr 1-1058 O═ Pyr 1-1059 S═ Pyr 1-1060 cPent Pyr 1-1061 cHex Pyr 1-1062 dioxo Pyr 1-1063 dioxa Pyr 1-1064 dithio Pyr 1-1065 dithia Pyr 1-1066 oxathio Pyr 1-1067 oxathia Pyr 1-1068 4-HM-dioxo Pyr 1-1069 4,5-diHM-dioxo Pyr 1-1070 4,5-diHE-dioxo Pyr 1-1071 5-OH-dioxa Pyr 1-1072 5-NHAc-dioxa Pyr 1-1073 5,5-diHM-dioxa Pyr 1-1074 H,H 2-F—Pyr 1-1075 O═ 2-F—Pyr 1-1076 S═ 2-F—Pyr 1-1077 cPent 2-F—Pyr 1-1078 cHex 2-F—Pyr 1-1079 dioxo 2-F—Pyr 1-1080 dioxa 2-F—Pyr 1-1081 dithio 2-F—Pyr 1-1082 dithia 2-F—Pyr 1-1083 oxathia 2-F—Pyr 1-1084 oxathia 2-F—Pyr 1-1085 4-HM-dioxo 2-F—Pyr 1-1086 4,5-diHM-dioxo 2-F—Pyr 1-1087 4,5-diHE-dioxo 2-F—Pyr 1-1088 5-OH-dioxa 2-F—Pyr 1-1089 5-NHAc-dioxa 2-F—Pyr 1-1090 5,5-diHM-dioxa 2-F—Pyr 1-1091 H,H 2-Cl—Pyr 1-1092 O═ 2-Cl—Pyr 1-1093 S═ 2-Cl—Pyr 1-1094 cPent 2-Cl—Pyr 1-1095 cHex 2-Cl—Pyr 1-1096 dioxo 2-Cl—Pyr 1-1097 dioxa 2-Cl—Pyr 1-1098 dithio 2-Cl—Pyr 1-1099 dithia 2-Cl—Pyr 1-1100 oxathio 2-Cl—Pyr 1-1101 oxathia 2-Cl—Pyr 1-1102 4-HM-dioxo 2-Cl—Pyr 1-1103 4,5-diHM-dioxo 2-Cl—Pyr 1-1104 4,5-diHE-dioxo 2-Cl—Pyr 1-1105 5-OH-dioxa 2-Cl—Pyr 1-1106 5-NHAc-dioxa 2-Cl—Pyr 1-1107 5,5-diHM-dioxa 2-Cl—Pyr 1-1108 H,H 2-Br—Pyr 1-1109 O═ 2-Br—Pyr 1-1110 S═ 2-Br—Pyr 1-1111 cPent 2-Br—Pyr 1-1112 cHex 2-Br—Pyr 1-1113 dioxo 2-Br—Pyr 1-1114 dioxa 2-Br—Pyr 1-1115 dithio 2-Br—Pyr 1-1116 dithia 2-Br—Pyr 1-1117 oxathio 2-Br—Pyr 1-1118 oxathia 2-Br—Pyr 1-1119 4-HM-dioxo 2-Br—Pyr 1-1120 4,5-diHM-dioxo 2-Br—Pyr 1-1121 4,5-diHE-dioxo 2-Br—Pyr 1-1122 5-OH-dioxa 2-Br—Pyr 1-1123 5-NHAc-dioxa 2-Br—Pyr 1-1124 5,5-diHM-dioxa 2-Br—Pyr 1-1125 H,H 2,5-diF—Pyr 1-1126 O═ 2,5-diF—Pyr 1-1127 S═ 2,5-diF—Pyr 1-1128 cPent 2,5-diF—Pyr 1-1129 cHex 2,5-diF—Pyr 1-1130 dioxo 2,5-diF—Pyr 1-1131 dioxa 2,5-diF—Pyr 1-1132 dithio 2,5-diF—Pyr 1-1133 dithia 2,5-diF—Pyr 1-1134 oxathio 2,5-diF—Pyr 1-1135 oxathia 2,5-diF—Pyr 1-1136 4-HM-dioxo 2,5-diF—Pyr 1-1137 4,5-diHM-dioxo 2,5-diF—Pyr 1-1138 4,5-diHE-dioxo 2,5-diF—Pyr 1-1139 5-OH-dioxa 2,5-diF—Pyr 1-1140 5-NHAc-dioxa 2,5-diF—Pyr 1-1141 5,5-diHM-dioxa 2,5-diF—Pyr 1-1142 H,H 2,5-diCl—Pyr 1-1143 O═ 2,5-diCl—Pyr 1-1144 S═ 2,5-diCl—Pyr 1-1145 cPent 2,5-diCl—Pyr 1-1146 cHex 2,5-diCl—Pyr 1-1147 dioxo 2,5-diCl—Pyr 1-1148 dioxa 2,5-diCl—Pyr 1-1149 dithio 2,5-diCl—Pyr 1-1150 dithia 2,5-diCl—Pyr 1-1151 oxathio 2,5-diCl—Pyr 1-1152 oxathia 2,5-diCl—Pyr 1-1153 4-HM-dioxo 2,5-diCl—Pyr 1-1154 4,5-diHM-dioxo 2,5-diCl—Pyr 1-1155 4,5-diHE-dioxo 2,5-diCl—Pyr 1-1156 5-OH-dioxa 2,5-diCl—Pyr 1-1157 5-NHAc-dioxa 2,5-diCl—Pyr 1-1158 5,5-diHM-dioxa 2,5-diCl—Pyr 1-1159 H,H 2,5-diBr—Pyr 1-1160 O═ 2,5-diBr—Pyr 1-1161 S═ 2,5-diBr—Pyr 1-1162 cPent 2,5-diBr—Pyr 1-1163 cHex 2,5-diBr—Pyr 1-1164 dioxo 2,5-diBr—Pyr 1-1165 dioxa 2,5-diBr—Pyr 1-1166 dithio 2,5-diBr—Pyr 1-1167 dithia 2,5-diBr—Pyr 1-1168 oxathio 2,5-diBr—Pyr 1-1169 oxathia 2,5-diBr—Pyr 1-1170 4-HM-dioxo 2,5-diBr—Pyr 1-1171 4,5-diHM-dioxo 2,5-diBr—Pyr 1-1172 4,5-diHE-dioxo 2,5-diBr—Pyr 1-1173 5-OH-dioxa 2,5-diBr—Pyr 1-1174 5-NHAc-dioxa 2,5-diBr—Pyr 1-1175 5,5-diHM-dioxa 2,5-diBr—Pyr 1-1176 H,H 2-Me—Pyr 1-1177 O═ 2-Me—Pyr 1-1178 S═ 2-Me—Pyr 1-1179 cPent 2-Me—Pyr 1-1180 cHex 2-Me—Pyr 1-1181 dioxo 2-Me—Pyr 1-1182 dioxa 2-Me—Pyr 1-1183 dithio 2-Me—Pyr 1-1184 dithia 2-Me—Pyr 1-1185 oxathio 2-Me—Pyr 1-1186 oxathia 2-Me—Pyr 1-1187 4-HM-dioxo 2-Me—Pyr 1-1188 4,5-diHM-dioxo 2-Me—Pyr 1-1189 4,5-diHE-dioxo 2-Me—Pyr 1-1190 5-OH-dioxa 2-Me—Pyr 1-1191 5-NHAc-dioxa 2-Me—Pyr 1-1192 5,5-diHM-dioxa 2-Me—Pyr 1-1193 H,H 2-Et—Pyr 1-1194 O═ 2-Et—Pyr 1-1195 S═ 2-Et—Pyr 1-1196 cPent 2-Et—Pyr 1-1197 cHex 2-Et—Pyr 1-1198 dioxo 2-Et—Pyr 1-1199 dioxa 2-Et—Pyr 1-1200 dithio 2-Et—Pyr 1-1201 dithia 2-Et—Pyr 1-1202 oxathio 2-Et—Pyr 1-1203 oxathia 2-Et—Pyr 1-1204 4-HM-dioxo 2-Et—Pyr 1-1205 4,5-diHM-dioxo 2-Et—Pyr 1-1206 4,5-diHE-dioxo 2-Et—Pyr 1-1207 5-OH-dioxa 2-Et—Pyr 1-1208 5-NHAc-dioxa 2-Et—Pyr 1-1209 5,5-diHM-dioxa 2-Et—Pyr 1-1210 H,H 2-nPr—Pyr 1-1211 O═ 2-nPr—Pyr 1-1212 S═ 2-nPr—Pyr 1-1213 cPent 2-nPr—Pyr 1-1214 cHex 2-nPr—Pyr 1-1215 dioxo 2-nPr—Pyr 1-1216 dioxa 2-nPr—Pyr 1-1217 dithio 2-nPr—Pyr 1-1218 dithia 2-nPr—Pyr 1-1219 oxathio 2-nPr—Pyr 1-1220 oxathia 2-nPr—Pyr 1-1221 4-HM-dioxo 2-nPr—Pyr 1-1222 4,5-diHM-dioxo 2-nPr—Pyr 1-1223 4,5-diHE-dioxo 2-nPr—Pyr 1-1224 5-OH-dioxa 2-nPr—Pyr 1-1225 5-NHAc-dioxa 2-nPr—Pyr 1-1226 5,5-diHM-dioxa 2-nPr—Pyr 1-1227 H,H 2-nBu—Pyr 1-1228 O═ 2-nBu—Pyr 1-1229 S═ 2-nBu—Pyr 1-1230 cPent 2-nBu—Pyr 1-1231 cHex 2-nBu—Pyr 1-1232 dioxo 2-nBu—Pyr 1-1233 dioxa 2-nBu—Pyr 1-1234 dithio 2-nBu—Pyr 1-1235 dithia 2-nBu—Pyr 1-1236 oxathio 2-nBu—Pyr 1-1237 oxathia 2-nBu—Pyr 1-1238 4-HM-dioxo 2-nBu—Pyr 1-1239 4,5-diHM-dioxo 2-nBu—Pyr 1-1240 4,5-diHE-dioxo 2-nBu—Pyr 1-1241 5-OH-dioxa 2-nBu—Pyr 1-1242 5-NHAc-dioxa 2-nBu—Pyr 1-1243 5,5-diHM-dioxa 2-nBu—Pyr 1-1244 H,H 2-nPent-Pyr 1-1245 O═ 2-nPent-Pyr 1-1246 S═ 2-nPent-Pyr 1-1247 cPent 2-nPent-Pyr 1-1248 cHex 2-nPent-Pyr 1-1249 dioxo 2-nPent-Pyr 1-1250 dioxa 2-nPent-Pyr 1-1251 dithio 2-nPent-Pyr 1-1252 dithia 2-nPent-Pyr 1-1253 oxathio 2-nPent-Pyr 1-1254 oxathia 2-nPent-Pyr 1-1255 4-HM-dioxo 2-nPent-Pyr 1-1256 4,5-diHM-dioxo 2-nPent-Pyr 1-1257 4,5-diHE-dioxo 2-nPent-Pyr 1-1258 5-OH-dioxa 2-nPent-Pyr 1-1259 5-NHAc-dioxa 2-nPent-Pyr 1-1260 5,5-diHM-dioxa 2-nPent-Pyr 1-1261 H,H 2-nHex—Pyr 1-1262 O═ 2-nHex—Pyr 1-1263 S═ 2-nHex—Pyr 1-1264 cPent 2-nHex—Pyr 1-1265 cHex 2-nHex—Pyr 1-1266 dioxo 2-nHex—Pyr 1-1267 dioxa 2-nHex—Pyr 1-1268 dithio 2-nHex—Pyr 1-1269 dithia 2-nHex—Pyr 1-1270 oxathio 2-nHex—Pyr 1-1271 oxathia 2-nHex—Pyr 1-1272 4-HM-dioxo 2-nHex—Pyr 1-1273 4,5-diHM-dioxo 2-nHex—Pyr 1-1274 4,5-diHE-dioxo 2-nHex—Pyr 1-1275 5-OH-dioxa 2-nHex—Pyr 1-1276 5-NHAc-dioxa 2-nHex—Pyr 1-1277 5,5-diHM-dioxa 2-nHex—Pyr 1-1278 H,H 2-nHept-Pyr 1-1279 O═ 2-nHept-Pyr 1-1280 S═ 2-nHept-Pyr 1-1281 cPent 2-nHept-Pyr 1-1282 cHex 2-nHept-Pyr 1-1283 dioxo 2-nHept-Pyr 1-1284 dioxa 2-nHept-Pyr 1-1285 dithio 2-nHept-Pyr 1-1286 dithia 2-nHept-Pyr 1-1287 oxathio 2-nHept-Pyr 1-1288 oxathia 2-nHept-Pyr 1-1289 4-HM-dioxo 2-nHept-Pyr 1-1290 4,5-diHM-dioxo 2-nHept-Pyr 1-1291 4,5-diHE-dioxo 2-nHept-Pyr 1-1292 5-OH-dioxa 2-nHept-Pyr 1-1293 5-NHAc-dioxa 2-nHept-Pyr 1-1294 5,5-diHM-dioxa 2-nHept-Pyr 1-1295 H,H 2-nOct-Pyr 1-1296 O═ 2-nOct-Pyr 1-1297 S═ 2-nOct-Pyr 1-1298 cPent 2-nOct-Pyr 1-1299 cHex 2-nOct-Pyr 1-1300 dioxo 2-nOct-Pyr 1-1301 dioxa 2-nOct-Pyr 1-1302 dithio 2-nOct-Pyr 1-1303 dithia 2-nOct-Pyr 1-1304 oxathio 2-nOct-Pyr 1-1305 oxathia 2-nOct-Pyr 1-1306 4-HM-dioxo 2-nOct-Pyr 1-1307 4,5-diHM-dioxo 2-nOct-Pyr 1-1308 4,5-diHE-dioxo 2-nOct-Pyr 1-1309 5-OH-dioxa 2-nOct-Pyr 1-1310 5-NHAc-dioxa 2-nOct-Pyr 1-1311 5,5-diHM-dioxa 2-nOct-Pyr 1-1312 H,H 2-cPrl-Pyr 1-1313 O═ 2-cPrl-Pyr 1-1314 S═ 2-cPrl-Pyr 1-1315 cPent 2-cPrl-Pyr 1-1316 cHex 2-cPrl-Pyr 1-1317 dioxo 2-cPrl-Pyr 1-1318 dioxa 2-cPrl-Pyr 1-1319 dithio 2-cPrl-Pyr 1-1320 dithia 2-cPrl-Pyr 1-1321 oxathio 2-cPrl-Pyr 1-1322 oxathia 2-cPrl-Pyr 1-1323 4-HM-dioxo 2-cPrl-Pyr 1-1324 4,5-diHM-dioxo 2-cPrl-Pyr 1-1325 4,5-diHE-dioxo 2-cPrl-Pyr 1-1326 5-OH-dioxa 2-cPrl-Pyr 1-1327 5-NHAc-dioxa 2-cPrl-Pyr 1-1328 5,5-diHM-dioxa 2-cPrl-Pyr 1-1329 H,H 2-Ph—Pyr 1-1330 O═ 2-Ph—Pyr 1-1331 S═ 2-Ph—Pyr 1-1332 cPent 2-Ph—Pyr 1-1333 cHex 2-Ph—Pyr 1-1334 dioxo 2-Ph—Pyr 1-1335 dioxa 2-Ph—Pyr 1-1336 dithio 2-Ph—Pyr 1-1337 dithia 2-Ph—Pyr 1-1338 oxathio 2-Ph—Pyr 1-1339 oxathia 2-Ph—Pyr 1-1340 4-HM-dioxo 2-Ph—Pyr 1-1341 4,5-diHM-dioxo 2-Ph—Pyr 1-1342 4,5-diHE-dioxo 2-Ph—Pyr 1-1343 5-OH-dioxa 2-Ph—Pyr 1-1344 5-NHAc-dioxa 2-Ph—Pyr 1-1345 5,5-diHM-dioxa 2-Ph—Pyr 1-1346 H,H 2,5-diMe—Pyr 1-1347 O═ 2,5-diMe—Pyr 1-1348 S═ 2,5-diMe—Pyr 1-1349 cPent 2,5-diMe—Pyr 1-1350 cHex 2,5-diMe—Pyr 1-1351 dioxo 2,5-diMe—Pyr 1-1352 dioxa 2,5-diMe—Pyr 1-1353 dithio 2,5-diMe—Pyr 1-1354 dithia 2,5-diMe—Pyr 1-1355 oxathio 2,5-diMe—Pyr 1-1356 oxathia 2,5-diMe—Pyr 1-1357 4-HM-dioxo 2,5-diMe—Pyr 1-1358 4,5-diHM-dioxo 2,5-diMe—Pyr 1-1359 4,5-diHE-dioxo 2,5-diMe—Pyr 1-1360 5-OH-dioxa 2,5-diMe—Pyr 1-1361 5-NHAc-dioxa 2,5-diMe—Pyr 1-1362 5,5-diHM-dioxa 2,5-diMe—Pyr 1-1363 O═ 2-Br—Ph 1-1364 S═ 2-Br—Ph 1-1365 cPr 2-Br—Ph 1-1366 cBu 2-Br—Ph 1-1367 cPent 2-Br—Ph 1-1368 cHex 2-Br—Ph 1-1369 cHept 2-Br—Ph 1-1370 oxi 2-Br—Ph 1-1371 oxe 2-Br—Ph 1-1372 oxo 2-Br—Ph 1-1373 oxa 2-Br—Ph 1-1374 dioxo 2-Br—Ph 1-1375 dioxa 2-Br—Ph 1-1376 dioxe 2-Br—Ph 1-1377 dithio 2-Br—Ph 1-1378 dithia 2-Br—Ph 1-1379 ring 1 2-Br—Ph 1-1380 ring 2 2-Br—Ph 1-1381 oxathio 2-Br—Ph 1-1382 oxathia 2-Br—Ph 1-1383 ozl 2-Br—Ph 1-1384 ozn 2-Br—Ph 1-1385 tzl 2-Br—Ph 1-1386 tzn 2-Br—Ph 1-1387 3-HM-cPent 2-Br—Ph 1-1388 4-HM-dioxo 2-Br—Ph 1-1389 4-HM-dithio 2-Br—Ph 1-1390 4-HM-oxathio 2-Br—Ph 1-1391 3,4-diHM-cPent 2-Br—Ph 1-1392 4,5-diHM-dioxo 2-Br—Ph 1-1393 4,5-diHM-dithio 2-Br—Ph 1-1394 4,5-diHM-oxathio 2-Br—Ph 1-1395 3,4-diHE-cPent 2-Br—Ph 1-1396 4,5-diHE-dioxo 2-Br—Ph 1-1397 4,5-diHE-dithio 2-Br—Ph 1-1398 4,5-diHE-oxathio 2-Br—Ph 1-1399 3-HE-cPent 2-Br—Ph 1-1400 4-HE-dioxo 2-Br—Ph 1-1401 4-HE-dithio 2-Br—Ph 1-1402 4-HE-oxathio 2-Br—Ph 1-1403 3-HP-cPent 2-Br—Ph 1-1404 4-HP-dioxo 2-Br—Ph 1-1405 4-HP-dithio 2-Br—Ph 1-1406 4-HP-oxathio 2-Br—Ph 1-1407 3-HB-cPent 2-Br—Ph 1-1408 4-HB-dioxo 2-Br—Ph 1-1409 4-HB-dithio 2-Br—Ph 1-1410 4-HB-oxathio 2-Br—Ph 1-1411 ring 3 2-Br—Ph 1-1412 ring 4 2-Br—Ph 1-1413 ring 5 2-Br—Ph 1-1414 ring 6 2-Br—Ph 1-1415 ring 7 2-Br—Ph 1-1416 ring 8 2-Br—Ph 1-1417 ring 9 2-Br—Ph 1-1418 ring 10 2-Br—Ph 1-1419 3,4-diCH₂NHAc-cPent 2-Br—Ph 1-1420 4,5-diCH₂NHAc-dioxo 2-Br—Ph 1-1421 4,5-diCH₂NHAc-dithio 2-Br—Ph 1-1422 4,5-diCH₂NHAc-oxathio 2-Br—Ph 1-1423 ring 11 2-Br—Ph 1-1424 ring 12 2-Br—Ph 1-1425 ring 13 2-Br—Ph 1-1426 ring 14 2-Br—Ph 1-1427 4-OH-cHex 2-Br—Ph 1-1428 5-OH-dioxa 2-Br—Ph 1-1429 5-OH-dithia 2-Br—Ph 1-1430 5-OH-oxathia 2-Br—Ph 1-1431 4-NHAc-cHex 2-Br—Ph 1-1432 5-NHAc-dioxa 2-Br—Ph 1-1433 5-NHAc-dithia 2-Br—Ph 1-1434 5-NHAc-oxathia 2-Br—Ph 1-1435 4,4-diMe-cHex 2-Br—Ph 1-1436 5,5-diMe-dioxa 2-Br—Ph 1-1437 5,5-diMe-dithia 2-Br—Ph 1-1438 5,5-diMe-oxathia 2-Br—Ph 1-1439 4,4-diHM-cHex 2-Br—Ph 1-1440 5,5-diHM-dioxa 2-Br—Ph 1-1441 5,5-diHM-dithia 2-Br—Ph 1-1442 5,5-diHM-oxathia 2-Br—Ph 1-1443 ring 15 2-Br—Ph 1-1444 ring 16 2-Br—Ph 1-1445 ring 17 2-Br—Ph 1-1446 ring 18 2-Br—Ph 1-1447 4,4-diCO₂Et-cHex 2-Br—Ph 1-1448 5,5-diCO₂Et-dioxa 2-Br—Ph 1-1449 5,5-diCO₂Et-dithia 2-Br—Ph 1-1450 5,5-diCO₂Et-oxathia 2-Br—Ph 1-1451 O═ 2-Cl-6-Me—Ph 1-1452 S═ 2-Cl-6-Me—Ph 1-1453 cPr 2-Cl-6-Me—Ph 1-1454 cBu 2-Cl-6-Me—Ph 1-1455 cPent 2-Cl-6-Me—Ph 1-1456 cHex 2-Cl-6-Me—Ph 1-1457 cHept 2-Cl-6-Me—Ph 1-1458 oxi 2-Cl-6-Me—Ph 1-1459 oxe 2-Cl-6-Me—Ph 1-1460 oxo 2-Cl-6-Me—Ph 1-1461 oxa 2-Cl-6-Me—Ph 1-1462 dioxo 2-Cl-6-Me—Ph 1-1463 dioxa 2-Cl-6-Me—Ph 1-1464 dioxe 2-Cl-6-Me—Ph 1-1465 dithio 2-Cl-6-Me—Ph 1-1466 dithia 2-Cl-6-Me—Ph 1-1467 ring 1 2-Cl-6-Me—Ph 1-1468 ring 2 2-Cl-6-Me—Ph 1-1469 oxathio 2-Cl-6-Me—Ph 1-1470 oxathia 2-Cl-6-Me—Ph 1-1471 ozl 2-Cl-6-Me—Ph 1-1472 ozn 2-Cl-6-Me—Ph 1-1473 tzl 2-Cl-6-Me—Ph 1-1474 tzn 2-Cl-6-Me—Ph 1-1475 3-HM-cPent 2-Cl-6-Me—Ph 1-1476 4-HM-dioxo 2-Cl-6-Me—Ph 1-1477 4-HM-dithio 2-Cl-6-Me—Ph 1-1478 4-HM-oxathio 2-Cl-6-Me—Ph 1-1479 3,4-diHM-cPent 2-Cl-6-Me—Ph 1-1480 4,5-diHM-dioxo 2-Cl-6-Me—Ph 1-1481 4,5-diHM-dithio 2-Cl-6-Me—Ph 1-1482 4,5-diHM-oxathio 2-Cl-6-Me—Ph 1-1483 3,4-diHE-cPent 2-Cl-6-Me—Ph 1-1484 4,5-diHE-dioxo 2-Cl-6-Me—Ph 1-1485 4,5-diHE-dithio 2-Cl-6-Me—Ph 1-1486 4,5-diHE-oxathio 2-Cl-6-Me—Ph 1-1487 3-HE-cPent 2-Cl-6-Me—Ph 1-1488 4-HE-dioxo 2-Cl-6-Me—Ph 1-1489 4-HE-dithio 2-Cl-6-Me—Ph 1-1490 4-HE-oxathio 2-Cl-6-Me—Ph 1-1491 3-HP-cPent 2-Cl-6-Me—Ph 1-1492 4-HP-dioxo 2-Cl-6-Me—Ph 1-1493 4-HP-dithio 2-Cl-6-Me—Ph 1-1494 4-HP-oxathio 2-Cl-6-Me—Ph 1-1495 3-HB-cPent 2-Cl-6-Me—Ph 1-1496 4-HB-dioxo 2-Cl-6-Me—Ph 1-1497 4-HB-dithio 2-Cl-6-Me—Ph 1-1498 4-HB-oxathio 2-Cl-6-Me—Ph 1-1499 ring 3 2-Cl-6-Me—Ph 1-1500 ring 4 2-Cl-6-Me—Ph 1-1501 ring 5 2-Cl-6-Me—Ph 1-1502 ring 6 2-Cl-6-Me—Ph 1-1503 ring 7 2-Cl-6-Me—Ph 1-1504 ring 8 2-Cl-6-Me—Ph 1-1505 ring 9 2-Cl-6-Me—Ph 1-1506 ring 10 2-Cl-6-Me—Ph 1-1507 3,4-diCH₂NHAc-cPent 2-Cl-6-Me—Ph 1-1508 4,5-diCH₂NHAc-dioxo 2-Cl-6-Me—Ph 1-1509 4,5-diCH₂NHAc-dithio 2-Cl-6-Me—Ph 1-1510 4,5-diCH₂NHAc-oxathio 2-Cl-6-Me—Ph 1-1511 ring 11 2-Cl-6-Me—Ph 1-1512 ring 12 2-Cl-6-Me—Ph 1-1513 ring 13 2-Cl-6-Me—Ph 1-1514 ring 14 2-Cl-6-Me—Ph 1-1515 4-OH-cHex 2-Cl-6-Me—Ph 1-1516 5-OH-dioxa 2-Cl-6-Me—Ph 1-1517 5-OH-dithia 2-Cl-6-Me—Ph 1-1518 5-OH-oxathia 2-Cl-6-Me—Ph 1-1519 4-NHAc-cHex 2-Cl-6-Me—Ph 1-1520 5-NHAc-dioxa 2-Cl-6-Me—Ph 1-1521 5-NHAc-dithia 2-Cl-6-Me—Ph 1-1522 5-NHAc-oxathia 2-Cl-6-Me—Ph 1-1523 4,4-diMe-cHex 2-Cl-6-Me—Ph 1-1524 5,5-diMe-dioxa 2-Cl-6-Me—Ph 1-1525 5,5-diMe-dithia 2-Cl-6-Me—Ph 1-1526 5,5-diMe-oxathia 2-Cl-6-Me—Ph 1-1527 4,4-diHM-cHex 2-Cl-6-Me—Ph 1-1528 5,5-diHM-dioxa 2-Cl-6-Me—Ph 1-1529 5,5-diHM-dithia 2-Cl-6-Me—Ph 1-1530 5,5-diHM-oxathia 2-Cl-6-Me—Ph 1-1531 ring 15 2-Cl-6-Me—Ph 1-1532 ring 16 2-Cl-6-Me—Ph 1-1533 ring 17 2-Cl-6-Me—Ph 1-1534 ring 18 2-Cl-6-Me—Ph 1-1535 4,4-diCO₂Et-cHex 2-Cl-6-Me—Ph 1-1536 5,5-diCO₂Et-dioxa 2-Cl-6-Me—Ph 1-1537 5,5-diCO₂Et-dithia 2-Cl-6-Me—Ph 1-1538 5,5-diCO₂Et-oxathia 2-Cl-6-Me—Ph 1-1539 O═ 2-Br-4-F—Ph 1-1540 S═ 2-Br-4-F—Ph 1-1541 cPr 2-Br-4-F—Ph 1-1542 cBu 2-Br-4-F—Ph 1-1543 cPent 2-Br-4-F—Ph 1-1544 cHex 2-Br-4-F—Ph 1-1545 cHept 2-Br-4-F—Ph 1-1546 oxi 2-Br-4-F—Ph 1-1547 oxe 2-Br-4-F—Ph 1-1548 oxo 2-Br-4-F—Ph 1-1549 oxa 2-Br-4-F—Ph 1-1550 dioxo 2-Br-4-F—Ph 1-1551 dioxa 2-Br-4-F—Ph 1-1552 dioxe 2-Br-4-F—Ph 1-1553 dithio 2-Br-4-F—Ph 1-1554 dithia 2-Br-4-F—Ph 1-1555 ring 1 2-Br-4-F—Ph 1-1556 ring 2 2-Br-4-F—Ph 1-1557 oxathio 2-Br-4-F—Ph 1-1558 oxathia 2-Br-4-F—Ph 1-1559 ozl 2-Br-4-F—Ph 1-1560 ozn 2-Br-4-F—Ph 1-1561 tzl 2-Br-4-F—Ph 1-1562 tzn 2-Br-4-F—Ph 1-1563 3-HM-cPent 2-Br-4-F—Ph 1-1564 4-HM-dioxo 2-Br-4-F—Ph 1-1565 4-HM-dithio 2-Br-4-F—Ph 1-1566 4-HM-oxathio 2-Br-4-F—Ph 1-1567 3,4-diHM-cPent 2-Br-4-F—Ph 1-1568 4,5-diHM-dioxo 2-Br-4-F—Ph 1-1569 4,5-diHM-dithio 2-Br-4-F—Ph 1-1570 4,5-diHM-oxathio 2-Br-4-F—Ph 1-1571 3,4-diHE-cPent 2-Br-4-F—Ph 1-1572 4,5-diHE-dioxo 2-Br-4-F—Ph 1-1573 4,5-diHE-dithio 2-Br-4-F—Ph 1-1574 4,5-diHE-oxathio 2-Br-4-F—Ph 1-1575 3-HE-cPent 2-Br-4-F—Ph 1-1576 4-HE-dioxo 2-Br-4-F—Ph 1-1577 4-HE-dithio 2-Br-4-F—Ph 1-1578 4-HE-oxathio 2-Br-4-F—Ph 1-1579 3-HP-cPent 2-Br-4-F—Ph 1-1580 4-HP-dioxo 2-Br-4-F—Ph 1-1581 4-HP-dithio 2-Br-4-F—Ph 1-1582 4-HP-oxathio 2-Br-4-F—Ph 1-1583 3-HB-cPent 2-Br-4-F—Ph 1-1584 4-HB-dioxo 2-Br-4-F—Ph 1-1585 4-HB-dithio 2-Br-4-F—Ph 1-1586 4-HB-oxathio 2-Br-4-F—Ph 1-1587 ring 3 2-Br-4-F—Ph 1-1588 ring 4 2-Br-4-F—Ph 1-1589 ring 5 2-Br-4-F—Ph 1-1590 ring 6 2-Br-4-F—Ph 1-1591 ring 7 2-Br-4-F—Ph 1-1592 ring 8 2-Br-4-F—Ph 1-1593 ring 9 2-Br-4-F—Ph 1-1594 ring 10 2-Br-4-F—Ph 1-1595 3,4-diCH₂NHAc-cPent 2-Br-4-F—Ph 1-1596 4,5-diCH₂NHAc-dioxo 2-Br-4-F—Ph 1-1597 4,5-diCH₂NHAc-dithio 2-Br-4-F—Ph 1-1598 4,5-diCH₂NHAc-oxathio 2-Br-4-F—Ph 1-1599 ring 11 2-Br-4-F—Ph 1-1600 ring 12 2-Br-4-F—Ph 1-1601 ring 13 2-Br-4-F—Ph 1-1602 ring 14 2-Br-4-F—Ph 1-1603 4-OH-cHex 2-Br-4-F—Ph 1-1604 5-OH-dioxa 2-Br-4-F—Ph 1-1605 5-OH-dithia 2-Br-4-F—Ph 1-1606 5-OH-oxathia 2-Br-4-F—Ph 1-1607 4-NHAc-cHex 2-Br-4-F—Ph 1-1608 5-NHAc-dioxa 2-Br-4-F—Ph 1-1609 5-NHAc-dithia 2-Br-4-F—Ph 1-1610 5-NHAc-oxathia 2-Br-4-F—Ph 1-1611 4,4-diMe-cHex 2-Br-4-F—Ph 1-1612 5,5-diMe-dioxa 2-Br-4-F—Ph 1-1613 5,5-diMe-dithia 2-Br-4-F—Ph 1-1614 5,5-diMe-oxathia 2-Br-4-F—Ph 1-1615 4,4-diHM-cHex 2-Br-4-F—Ph 1-1616 5,5-diHM-dioxa 2-Br-4-F—Ph 1-1617 5,5-diHM-dithia 2-Br-4-F—Ph 1-1618 5,5-diHM-oxathia 2-Br-4-F—Ph 1-1619 ring 15 2-Br-4-F—Ph 1-1620 ring 16 2-Br-4-F—Ph 1-1621 ring 17 2-Br-4-F—Ph 1-1622 ring 18 2-Br-4-F—Ph 1-1623 4,4-diCO₂Et-cHex 2-Br-4-F—Ph 1-1624 5,5-diCO₂Et-dioxa 2-Br-4-F—Ph 1-1625 5,5-diCO₂Et-dithia 2-Br-4-F—Ph 1-1626 5,5-diCO₂Et-oxathia 2-Br-4-F—Ph 1-1627 O═ 2-nPent-Ph 1-1628 S═ 2-nPent-Ph 1-1629 cPr 2-nPent-Ph 1-1630 cBu 2-nPent-Ph 1-1631 cPent 2-nPent-Ph 1-1632 cHex 2-nPent-Ph 1-1633 cHept 2-nPent-Ph 1-1634 oxi 2-nPent-Ph 1-1635 oxe 2-nPent-Ph 1-1636 oxo 2-nPent-Ph 1-1637 oxa 2-nPent-Ph 1-1638 dioxo 2-nPent-Ph 1-1639 dioxa 2-nPent-Ph 1-1640 dioxe 2-nPent-Ph 1-1641 dithio 2-nPent-Ph 1-1642 dithia 2-nPent-Ph 1-1643 ring 1 2-nPent-Ph 1-1644 ring 2 2-nPent-Ph 1-1645 oxathio 2-nPent-Ph 1-1646 oxathia 2-nPent-Ph 1-1647 ozl 2-nPent-Ph 1-1648 ozn 2-nPent-Ph 1-1649 tzl 2-nPent-Ph 1-1650 tzn 2-nPent-Ph 1-1651 3-HM-cPent 2-nPent-Ph 1-1652 4-HM-dioxo 2-nPent-Ph 1-1653 4-HM-dithio 2-nPent-Ph 1-1654 4-HM-oxathio 2-nPent-Ph 1-1655 3,4-diHM-cPent 2-nPent-Ph 1-1656 4,5-diHM-dioxo 2-nPent-Ph 1-1657 4,5-diHM-dithio 2-nPent-Ph 1-1658 4,5-diHM-oxathio 2-nPent-Ph 1-1659 3,4-diHE-cPent 2-nPent-Ph 1-1660 4,5-diHE-dioxo 2-nPent-Ph 1-1661 4,5-diHE-dithio 2-nPent-Ph 1-1662 4,5-diHE-oxathio 2-nPent-Ph 1-1663 3-HE-cPent 2-nPent-Ph 1-1664 4-HE-dioxo 2-nPent-Ph 1-1665 4-HE-dithio 2-nPent-Ph 1-1666 4-HE-oxathio 2-nPent-Ph 1-1667 3-HP-cPent 2-nPent-Ph 1-1668 4-HP-dioxo 2-nPent-Ph 1-1669 4-HP-dithio 2-nPent-Ph 1-1670 4-HP-oxathio 2-nPent-Ph 1-1671 3-HB-cPent 2-nPent-Ph 1-1672 4-HB-dioxo 2-nPent-Ph 1-1673 4-HB-dithio 2-nPent-Ph 1-1674 4-HB-oxathio 2-nPent-Ph 1-1675 ring 3 2-nPent-Ph 1-1676 ring 4 2-nPent-Ph 1-1677 ring 5 2-nPent-Ph 1-1678 ring 6 2-nPent-Ph 1-1679 ring 7 2-nPent-Ph 1-1680 ring 8 2-nPent-Ph 1-1681 ring 9 2-nPent-Ph 1-1682 ring 10 2-nPent-Ph 1-1683 3,4-diCH₂NHAc-cPent 2-nPent-Ph 1-1684 4,5-diCH₂NHAc-dioxo 2-nPent-Ph 1-1685 4,5-diCH₂NHAc-dithio 2-nPent-Ph 1-1686 4,5-diCH₂NHAc-oxathio 2-nPent-Ph 1-1687 ring 11 2-nPent-Ph 1-1688 ring 12 2-nPent-Ph 1-1689 ring 13 2-nPent-Ph 1-1690 ring 14 2-nPent-Ph 1-1691 4-OH-cHex 2-nPent-Ph 1-1692 5-OH-dioxa 2-nPent-Ph 1-1693 5-OH-dithia 2-nPent-Ph 1-1694 5-OH-oxathia 2-nPent-Ph 1-1695 4-NHAc-cHex 2-nPent-Ph 1-1696 5-NHAc-dioxa 2-nPent-Ph 1-1697 5-NHAc-dithia 2-nPent-Ph 1-1698 5-NHAc-oxathia 2-nPent-Ph 1-1699 4,4-diMe-cHex 2-nPent-Ph 1-1700 5,5-diMe-dioxa 2-nPent-Ph 1-1701 5,5-diMe-dithia 2-nPent-Ph 1-1702 5,5-diMe-oxathia 2-nPent-Ph 1-1703 4,4-diHM-cHex 2-nPent-Ph 1-1704 5,5-diHM-dioxa 2-nPent-Ph 1-1705 5,5-diHM-dithia 2-nPent-Ph 1-1706 5,5-diHM-oxathia 2-nPent-Ph 1-1707 ring 15 2-nPent-Ph 1-1708 ring 16 2-nPent-Ph 1-1709 ring 17 2-nPent-Ph 1-1710 ring 18 2-nPent-Ph 1-1711 4,4-diCO₂Et-cHex 2-nPent-Ph 1-1712 5,5-diCO₂Et-dioxa 2-nPent-Ph 1-1713 5,5-diCO₂Et-dithia 2-nPent-Ph 1-1714 5,5-diCO₂Et-oxathia 2-nPent-Ph 1-1715 O═ 4-F-2-nPent-Ph 1-1716 S═ 4-F-2-nPent-Ph 1-1717 cPr 4-F-2-nPent-Ph 1-1718 cBu 4-F-2-nPent-Ph 1-1719 cPent 4-F-2-nPent-Ph 1-1720 cHex 4-F-2-nPent-Ph 1-1721 cHept 4-F-2-nPent-Ph 1-1722 oxi 4-F-2-nPent-Ph 1-1723 oxe 4-F-2-nPent-Ph 1-1724 oxo 4-F-2-nPent-Ph 1-1725 oxa 4-F-2-nPent-Ph 1-1726 dioxo 4-F-2-nPent-Ph 1-1727 dioxa 4-F-2-nPent-Ph 1-1728 dioxe 4-F-2-nPent-Ph 1-1729 dithio 4-F-2-nPent-Ph 1-1730 dithia 4-F-2-nPent-Ph 1-1731 ring 1 4-F-2-nPent-Ph 1-1732 ring 2 4-F-2-nPent-Ph 1-1733 oxathio 4-F-2-nPent-Ph 1-1734 oxathia 4-F-2-nPent-Ph 1-1735 ozl 4-F-2-nPent-Ph 1-1736 ozn 4-F-2-nPent-Ph 1-1737 tzl 4-F-2-nPent-Ph 1-1738 tzn 4-F-2-nPent-Ph 1-1739 3-HM-cPent 4-F-2-nPent-Ph 1-1740 4-HM-dioxo 4-F-2-nPent-Ph 1-1741 4-HM-dithio 4-F-2-nPent-Ph 1-1742 4-HM-oxathio 4-F-2-nPent-Ph 1-1743 3,4-diHM-cPent 4-F-2-nPent-Ph 1-1744 4,5-diHM-dioxo 4-F-2-nPent-Ph 1-1745 4,5-diHM-dithio 4-F-2-nPent-Ph 1-1746 4,5-diHM-oxathio 4-F-2-nPent-Ph 1-1747 3,4-diHE-cPent 4-F-2-nPent-Ph 1-1748 4,5-diHE-dioxo 4-F-2-nPent-Ph 1-1749 4,5-diHE-dithio 4-F-2-nPent-Ph 1-1750 4,5-diHE-oxathio 4-F-2-nPent-Ph 1-1751 3-HE-cPent 4-F-2-nPent-Ph 1-1752 4-HE-dioxo 4-F-2-nPent-Ph 1-1753 4-HE-dithio 4-F-2-nPent-Ph 1-1754 4-HE-oxathio 4-F-2-nPent-Ph 1-1755 3-HP-cPent 4-F-2-nPent-Ph 1-1756 4-HP-dioxo 4-F-2-nPent-Ph 1-1757 4-HP-dithio 4-F-2-nPent-Ph 1-1758 4-HP-oxathio 4-F-2-nPent-Ph 1-1759 3-HB-cPent 4-F-2-nPent-Ph 1-1760 4-HB-dioxo 4-F-2-nPent-Ph 1-1761 4-HB-dithio 4-F-2-nPent-Ph 1-1762 4-HB-oxathio 4-F-2-nPent-Ph 1-1763 ring 3 4-F-2-nPent-Ph 1-1764 ring 4 4-F-2-nPent-Ph 1-1765 ring 5 4-F-2-nPent-Ph 1-1766 ring 6 4-F-2-nPent-Ph 1-1767 ring 7 4-F-2-nPent-Ph 1-1768 ring 8 4-F-2-nPent-Ph 1-1769 ring 9 4-F-2-nPent-Ph 1-1770 ring 10 4-F-2-nPent-Ph 1-1771 3,4-diCH₂NHAc-cPent 4-F-2-nPent-Ph 1-1772 4,5-diCH₂NHAc-dioxo 4-F-2-nPent-Ph 1-1773 4,5-diCH₂NHAc-dithio 4-F-2-nPent-Ph 1-1774 4,5-diCH₂NHAc-oxathio 4-F-2-nPent-Ph 1-1775 ring 11 4-F-2-nPent-Ph 1-1776 ring 12 4-F-2-nPent-Ph 1-1777 ring 13 4-F-2-nPent-Ph 1-1778 ring 14 4-F-2-nPent-Ph 1-1779 4-OH-cHex 4-F-2-nPent-Ph 1-1780 5-OH-dioxa 4-F-2-nPent-Ph 1-1781 5-OH-dithia 4-F-2-nPent-Ph 1-1782 5-OH-oxathia 4-F-2-nPent-Ph 1-1783 4-NHAc-cHex 4-F-2-nPent-Ph 1-1784 5-NHAc-dioxa 4-F-2-nPent-Ph 1-1785 5-NHAc-dithia 4-F-2-nPent-Ph 1-1786 5-NHAc-oxathia 4-F-2-nPent-Ph 1-1787 4,4-diMe-cHex 4-F-2-nPent-Ph 1-1788 5,5-diMe-dioxa 4-F-2-nPent-Ph 1-1789 5,5-diMe-dithia 4-F-2-nPent-Ph 1-1790 5,5-diMe-oxathia 4-F-2-nPent-Ph 1-1791 4,4-diHM-cHex 4-F-2-nPent-Ph 1-1792 5,5-diHM-dioxa 4-F-2-nPent-Ph 1-1793 5,5-diHM-dithia 4-F-2-nPent-Ph 1-1794 5,5-diHM-oxathia 4-F-2-nPent-Ph 1-1795 ring 15 4-F-2-nPent-Ph 1-1796 ring 16 4-F-2-nPent-Ph 1-1797 ring 17 4-F-2-nPent-Ph 1-1798 ring 18 4-F-2-nPent-Ph 1-1799 4,4-diCO₂Et-cHex 4-F-2-nPent-Ph 1-1800 5,5-diCO₂Et-dioxa 4-F-2-nPent-Ph 1-1801 5,5-diCO₂Et-dithia 4-F-2-nPent-Ph 1-1802 5,5-diCO₂Et-oxathia 4-F-2-nPent-Ph 1-1803 O═ 2-nOct-Ph 1-1804 S═ 2-nOct-Ph 1-1805 cPr 2-nOct-Ph 1-1806 cBu 2-nOct-Ph 1-1807 cPent 2-nOct-Ph 1-1808 cHex 2-nOct-Ph 1-1809 cHept 2-nOct-Ph 1-1810 oxi 2-nOct-Ph 1-1811 oxe 2-nOct-Ph 1-1812 oxo 2-nOct-Ph 1-1813 oxa 2-nOct-Ph 1-1814 dioxo 2-nOct-Ph 1-1815 dioxa 2-nOct-Ph 1-1816 dioxe 2-nOct-Ph 1-1817 dithio 2-nOct-Ph 1-1818 dithia 2-nOct-Ph 1-1819 ring 1 2-nOct-Ph 1-1820 ring 2 2-nOct-Ph 1-1821 oxathio 2-nOct-Ph 1-1822 oxathia 2-nOct-Ph 1-1823 ozl 2-nOct-Ph 1-1824 ozn 2-nOct-Ph 1-1825 tzl 2-nOct-Ph 1-1826 tzn 2-nOct-Ph 1-1827 3-HM-cPent 2-nOct-Ph 1-1828 4-HM-dioxo 2-nOct-Ph 1-1829 4-HM-dithio 2-nOct-Ph 1-1830 4-HM-oxathio 2-nOct-Ph 1-1831 3,4-diHM-cPent 2-nOct-Ph 1-1832 4,5-diHM-dioxo 2-nOct-Ph 1-1833 4,5-diHM-dithio 2-nOct-Ph 1-1834 4,5-diHM-oxathio 2-nOct-Ph 1-1835 3,4-diHE-cPent 2-nOct-Ph 1-1836 4,5-diHE-dioxo 2-nOct-Ph 1-1837 4,5-diHE-dithio 2-nOct-Ph 1-1838 4,5-diHE-oxathio 2-nOct-Ph 1-1839 3-HE-cPent 2-nOct-Ph 1-1840 4-HE-dioxo 2-nOct-Ph 1-1841 4-HE-dithio 2-nOct-Ph 1-1842 4-HE-oxathio 2-nOct-Ph 1-1843 3-HP-cPent 2-nOct-Ph 1-1844 4-HP-dioxo 2-nOct-Ph 1-1845 4-HP-dithio 2-nOct-Ph 1-1846 4-HP-oxathio 2-nOct-Ph 1-1847 3-HB-cPent 2-nOct-Ph 1-1848 4-HB-dioxo 2-nOct-Ph 1-1849 4-HB-dithio 2-nOct-Ph 1-1850 4-HB-oxathio 2-nOct-Ph 1-1851 ring 3 2-nOct-Ph 1-1852 ring 4 2-nOct-Ph 1-1853 ring 5 2-nOct-Ph 1-1854 ring 6 2-nOct-Ph 1-1855 ring 7 2-nOct-Ph 1-1856 ring 8 2-nOct-Ph 1-1857 ring 9 2-nOct-Ph 1-1858 ring 10 2-nOct-Ph 1-1859 3,4-diCH₂NHAc-cPent 2-nOct-Ph 1-1860 4,5-diCH₂NHAc-dioxo 2-nOct-Ph 1-1861 4,5-diCH₂NHAc-dithio 2-nOct-Ph 1-1862 4,5-diCH₂NHAc-oxathio 2-nOct-Ph 1-1863 ring 11 2-nOct-Ph 1-1864 ring 12 2-nOct-Ph 1-1865 ring 13 2-nOct-Ph 1-1866 ring 14 2-nOct-Ph 1-1867 4-OH-cHex 2-nOct-Ph 1-1868 5-OH-dioxa 2-nOct-Ph 1-1869 5-OH-dithia 2-nOct-Ph 1-1870 5-OH-oxathia 2-nOct-Ph 1-1871 4-NHAc-cHex 2-nOct-Ph 1-1872 5-NHAc-dioxa 2-nOct-Ph 1-1873 5-NHAc-dithia 2-nOct-Ph 1-1874 5-NHAc-oxathia 2-nOct-Ph 1-1875 4,4-diMe-cHex 2-nOct-Ph 1-1876 5,5-diMe-dioxa 2-nOct-Ph 1-1877 5,5-diMe-dithia 2-nOct-Ph 1-1878 5,5-diMe-oxathia 2-nOct-Ph 1-1879 4,4-diHM-cHex 2-nOct-Ph 1-1880 5,5-diHM-dioxa 2-nOct-Ph 1-1881 5,5-diHM-dithia 2-nOct-Ph 1-1882 5,5-diHM-oxathia 2-nOct-Ph 1-1883 ring 15 2-nOct-Ph 1-1884 ring 16 2-nOct-Ph 1-1885 ring 17 2-nOct-Ph 1-1886 ring 18 2-nOct-Ph 1-1887 4,4-diCO₂Et-cHex 2-nOct-Ph 1-1888 5,5-diCO₂Et-dioxa 2-nOct-Ph 1-1889 5,5-diCO₂Et-dithia 2-nOct-Ph 1-1890 5,5-diCO₂Et-oxathia 2-nOct-Ph 1-1891 O═ 4-F-2-nOct-Ph 1-1892 S═ 4-F-2-nOct-Ph 1-1893 cPr 4-F-2-nOct-Ph 1-1894 cBu 4-F-2-nOct-Ph 1-1895 cPent 4-F-2-nOct-Ph 1-1896 cHex 4-F-2-nOct-Ph 1-1897 cHept 4-F-2-nOct-Ph 1-1898 oxi 4-F-2-nOct-Ph 1-1899 oxe 4-F-2-nOct-Ph 1-1900 oxo 4-F-2-nOct-Ph 1-1901 oxa 4-F-2-nOct-Ph 1-1902 diaxo 4-F-2-nOct-Ph 1-1903 dioxa 4-F-2-nOct-Ph 1-1904 dioxe 4-F-2-nOct-Ph 1-1905 dithio 4-F-2-nOct-Ph 1-1906 dithia 4-F-2-nOct-Ph 1-1907 ring 1 4-F-2-nOct-Ph 1-1908 ring 2 4-F-2-nOct-Ph 1-1909 oxathio 4-F-2-nOct-Ph 1-1910 oxathia 4-F-2-nOct-Ph 1-1911 ozl 4-F-2-nOct-Ph 1-1912 ozn 4-F-2-nOct-Ph 1-1913 tzl 4-F-2-nOct-Ph 1-1914 tzn 4-F-2-nOct-Ph 1-1915 3-HM-cPent 4-F-2-nOct-Ph 1-1916 4-HM-dioxo 4-F-2-nOct-Ph 1-1917 4-HM-dithio 4-F-2-nOct-Ph 1-1918 4-HM-oxathio 4-F-2-nOct-Ph 1-1919 3,4-diHM-cPent 4-F-2-nOct-Ph 1-1920 4,5-diHM-dioxo 4-F-2-nOct-Ph 1-1921 4,5-diHM-dithio 4-F-2-nOct-Ph 1-1922 4,5-diHM-oxathio 4-F-2-nOct-Ph 1-1923 3,4-diHE-cPent 4-F-2-nOct-Ph 1-1924 4,5-diHE-dioxo 4-F-2-nOct-Ph 1-1925 4,5-diHE-dithio 4-F-2-nOct-Ph 1-1926 4,5-diHE-oxathio 4-F-2-nOct-Ph 1-1927 3-HE-cPent 4-F-2-nOct-Ph 1-1928 4-HE-dioxo 4-F-2-nOct-Ph 1-1929 4-HE-dithio 4-F-2-nOct-Ph 1-1930 4-HE-oxathio 4-F-2-nOct-Ph 1-1931 3-HP-cPent 4-F-2-nOct-Ph 1-1932 4-HP-dioxo 4-F-2-nOct-Ph 1-1933 4-HP-dithio 4-F-2-nOct-Ph 1-1934 4-HP-oxathio 4-F-2-nOct-Ph 1-1935 3-HB-cPent 4-F-2-nOct-Ph 1-1936 4-HB-dioxo 4-F-2-nOct-Ph 1-1937 4-HB-dithio 4-F-2-nOct-Ph 1-1938 4-HB-oxathio 4-F-2-nOct-Ph 1-1939 ring 3 4-F-2-nOct-Ph 1-1940 ring 4 4-F-2-nOct-Ph 1-1941 ring 5 4-F-2-nOct-Ph 1-1942 ring 6 4-F-2-nOct-Ph 1-1943 ring 7 4-F-2-nOct-Ph 1-1944 ring 8 4-F-2-nOct-Ph 1-1945 ring 9 4-F-2-nOct-Ph 1-1946 ring 10 4-F-2-nOct-Ph 1-1947 3,4-diCH₂NHAc-cPent 4-F-2-nOct-Ph 1-1948 4,5-diCH₂NHAc-dioxo 4-F-2-nOct-Ph 1-1949 4,5-diCH₂NHAc-dithio 4-F-2-nOct-Ph 1-1950 4,5-diCH₂NHAc-oxathio 4-F-2-nOct-Ph 1-1951 ring 11 4-F-2-nOct-Ph 1-1952 ring 12 4-F-2-nOct-Ph 1-1953 ring 13 4-F-2-nOct-Ph 1-1954 ring 14 4-F-2-nOct-Ph 1-1955 4-OH-cHex 4-F-2-nOct-Ph 1-1956 5-OH-dioxa 4-F-2-nOct-Ph 1-1957 5-OH-dithia 4-F-2-nOct-Ph 1-1958 5-OH-oxathia 4-F-2-nOct-Ph 1-1959 4-NHAc-cHex 4-F-2-nOct-Ph 1-1960 5-NHAc-dioxa 4-F-2-nOct-Ph 1-1961 5-NHAc-dithia 4-F-2-nOct-Ph 1-1962 5-NHAc-oxathia 4-F-2-nOct-Ph 1-1963 4,4-diMe-cHex 4-F-2-nOct-Ph 1-1964 5,5-diMe-dioxa 4-F-2-nOct-Ph 1-1965 5,5-diMe-dithia 4-F-2-nOct-Ph 1-1966 5,5-diMe-oxathia 4-F-2-nOct-Ph 1-1967 4,4-diHM-cHex 4-F-2-nOct-Ph 1-1968 5,5-diHM-dioxa 4-F-2-nOct-Ph 1-1969 5,5-diHM-dithia 4-F-2-nOct-Ph 1-1970 5,5-diHM-oxathia 4-F-2-nOct-Ph 1-1971 ring 15 4-F-2-nOct-Ph 1-1972 ring 16 4-F-2-nOct-Ph 1-1973 ring 17 4-F-2-nOct-Ph 1-1974 ring 18 4-F-2-nOct-Ph 1-1975 4,4-diCO₂Et-cHex 4-F-2-nOct-Ph 1-1976 5,5-diCO₂Et-dioxa 4-F-2-nOct-Ph 1-1977 5,5-diCO₂Et-dithia 4-F-2-nOct-Ph 1-1978 O═ 2-nPr—Ph 1-1979 S═ 2-nPr—Ph 1-1980 cPr 2-nPr—Ph 1-1981 cBu 2-nPr—Ph 1-1982 cPent 2-nPr—Ph 1-1983 cHex 2-nPr—Ph 1-1984 cHept 2-nPr—Ph 1-1985 oxi 2-nPr—Ph 1-1986 oxe 2-nPr—Ph 1-1987 oxo 2-nPr—Ph 1-1988 oxa 2-nPr—Ph 1-1989 dioxo 2-nPr—Ph 1-1990 dioxa 2-nPr—Ph 1-1991 dioxe 2-nPr—Ph 1-1992 dithio 2-nPr—Ph 1-1993 dithia 2-nPr—Ph 1-1994 ring 1 2-nPr—Ph 1-1995 ring 2 2-nPr—Ph 1-1996 oxathio 2-nPr—Ph 1-1997 oxathia 2-nPr—Ph 1-1998 ozl 2-nPr—Ph 1-1999 ozn 2-nPr—Ph 1-2000 tzl 2-nPr—Ph 1-2001 tzn 2-nPr—Ph 1-2002 3-HM-cPent 2-nPr—Ph 1-2003 4-HM-dioxo 2-nPr—Ph 1-2004 4-HM-dithio 2-nPr—Ph 1-2005 4-HM-oxathio 2-nPr—Ph 1-2006 3,4-diHM-cPent 2-nPr—Ph 1-2007 4,5-diHM-dioxo 2-nPr—Ph 1-2008 4,5-diHM-dithio 2-nPr—Ph 1-2009 4,5-diHM-oxathio 2-nPr—Ph 1-2010 3,4-diHE-cPent 2-nPr—Ph 1-2011 4,5-diHE-dioxo 2-nPr—Ph 1-2012 4,5-diHE-dithio 2-nPr—Ph 1-2013 4,5-diHE-oxathio 2-nPr—Ph 1-2014 3-HE-cPent 2-nPr—Ph 1-2015 4-HE-dioxo 2-nPr—Ph 1-2016 4-HE-dithio 2-nPr—Ph 1-2017 4-HE-oxathio 2-nPr—Ph 1-2018 3-HP-cPent 2-nPr—Ph 1-2019 4-HP-dioxo 2-nPr—Ph 1-2020 4-HP-dithio 2-nPr—Ph 1-2021 4-HP-oxathio 2-nPr—Ph 1-2022 3-HB-cPent 2-nPr—Ph 1-2023 4-HB-dioxo 2-nPr—Ph 1-2024 4-HB-dithio 2-nPr—Ph 1-2025 4-HB-oxathio 2-nPr—Ph 1-2026 ring 3 2-nPr—Ph 1-2027 ring 4 2-nPr—Ph 1-2028 ring 5 2-nPr—Ph 1-2029 ring 6 2-nPr—Ph 1-2030 ring 7 2-nPr—Ph 1-2031 ring 8 2-nPr—Ph 1-2032 ring 9 2-nPr—Ph 1-2033 ring 10 2-nPr—Ph 1-2034 3,4-diCH₂NHAc-cPent 2-nPr—Ph 1-2035 4,5-diCH₂NHAc-dioxo 2-nPr—Ph 1-2036 4,5-diCH₂NHAc-dithio 2-nPr—Ph 1-2037 4,5-diCH₂NHAc-oxathio 2-nPr—Ph 1-2038 ring 11 2-nPr—Ph 1-2039 ring 12 2-nPr—Ph 1-2040 ring 13 2-nPr—Ph 1-2041 ring 14 2-nPr—Ph 1-2042 4-OH-cHex 2-nPr—Ph 1-2043 5-OH-dioxa 2-nPr—Ph 1-2044 5-OH-dithia 2-nPr—Ph 1-2045 5-OH-oxathia 2-nPr—Ph 1-2046 4-NHAc-cHex 2-nPr—Ph 1-2047 5-NHAc-dioxa 2-nPr—Ph 1-2048 5-NHAc-dithia 2-nPr—Ph 1-2049 5-NHAc-oxathia 2-nPr—Ph 1-2050 4,4-diMe-cHex 2-nPr—Ph 1-2051 5,5-diMe-dioxa 2-nPr—Ph 1-2052 5,5-diMe-dithia 2-nPr—Ph 1-2053 5,5-diMe-oxathia 2-nPr—Ph 1-2054 4,4-diHM-cHex 2-nPr—Ph 1-2055 5,5-diHM-dioxa 2-nPr—Ph 1-2056 5,5-diHM-dithia 2-nPr—Ph 1-2057 5,5-diHM-oxathia 2-nPr—Ph 1-2058 ring 15 2-nPr—Ph 1-2059 ring 16 2-nPr—Ph 1-2060 ring 17 2-nPr—Ph 1-2061 ring 18 2-nPr—Ph 1-2062 4,4-diCO₂Et-cHex 2-nPr—Ph 1-2063 5,5-diCO₂Et-dioxa 2-nPr—Ph 1-2064 5,5-diCO₂Et-dithia 2-nPr—Ph 1-2065 5,5-diCO₂Et-oxathia 2-nPr—Ph 1-2066 O═ 4-F-2-nPr—Ph 1-2067 S═ 4-F-2-nPr—Ph 1-2068 cPr 4-F-2-nPr—Ph 1-2069 cBu 4-F-2-nPr—Ph 1-2070 cPent 4-F-2-nPr—Ph 1-2071 cHex 4-F-2-nPr—Ph 1-2072 cHept 4-F-2-nPr—Ph 1-2073 oxi 4-F-2-nPr—Ph 1-2074 oxe 4-F-2-nPr—Ph 1-2075 oxo 4-F-2-nPr—Ph 1-2076 oxa 4-F-2-nPr—Ph 1-2077 dioxo 4-F-2-nPr—Ph 1-2078 dioxa 4-F-2-nPr—Ph 1-2079 dioxe 4-F-2-nPr—Ph 1-2080 dithio 4-F-2-nPr—Ph 1-2081 dithia 4-F-2-nPr—Ph 1-2082 ring 1 4-F-2-nPr—Ph 1-2083 ring 2 4-F-2-nPr—Ph 1-2084 oxathio 4-F-2-nPr—Ph 1-2085 oxathia 4-F-2-nPr—Ph 1-2086 ozl 4-F-2-nPr—Ph 1-2087 ozn 4-F-2-nPr—Ph 1-2088 tzl 4-F-2-nPr—Ph 1-2089 tzn 4-F-2-nPr—Ph 1-2090 3-HM-cPent 4-F-2-nPr—Ph 1-2091 4-HM-dioxo 4-F-2-nPr—Ph 1-2092 4-HM-dithio 4-F-2-nPr—Ph 1-2093 4-HM-oxathio 4-F-2-nPr—Ph 1-2094 3,4-diHM-cPent 4-F-2-nPr—Ph 1-2095 4,5-diHM-dioxo 4-F-2-nPr—Ph 1-2096 4,5-diHM-dithio 4-F-2-nPr—Ph 1-2097 4,5-diHM-oxathio 4-F-2-nPr—Ph 1-2098 3,4-diHE-cPent 4-F-2-nPr—Ph 1-2099 4,5-diHE-dioxo 4-F-2-nPr—Ph 1-2100 4,5-diHE-dithio 4-F-2-nPr—Ph 1-2101 4,5-diHE-oxathio 4-F-2-nPr—Ph 1-2102 3-HE-cPent 4-F-2-nPr—Ph 1-2103 4-HE-dioxo 4-F-2-nPr—Ph 1-2104 4-HE-dithio 4-F-2-nPr—Ph 1-2105 4-HE-oxathio 4-F-2-nPr—Ph 1-2106 3-HP-cPent 4-F-2-nPr—Ph 1-2107 4-HP-dioxo 4-F-2-nPr—Ph 1-2108 4-HP-dithio 4-F-2-nPr—Ph 1-2109 4-HP-oxathio 4-F-2-nPr—Ph 1-2110 3-HB-cPent 4-F-2-nPr—Ph 1-2111 4-HB-dioxo 4-F-2-nPr—Ph 1-2112 4-HB-dithio 4-F-2-nPr—Ph 1-2113 4-HB-oxathio 4-F-2-nPr—Ph 1-2114 ring 3 4-F-2-nPr—Ph 1-2115 ring 4 4-F-2-nPr—Ph 1-2116 ring 5 4-F-2-nPr—Ph 1-2117 ring 6 4-F-2-nPr—Ph 1-2118 ring 7 4-F-2-nPr—Ph 1-2119 ring 8 4-F-2-nPr—Ph 1-2120 ring 9 4-F-2-nPr—Ph 1-2121 ring 10 4-F-2-nPr—Ph 1-2122 3,4-diCH₂NHAc-cPent 4-F-2-nPr—Ph 1-2123 4,5-diCH₂NHAc-dioxo 4-F-2-nPr—Ph 1-2124 4,5-diCH₂NHAc-dithio 4-F-2-nPr—Ph 1-2125 4,5-diCH₂NHAc-oxathio 4-F-2-nPr—Ph 1-2126 ring 11 4-F-2-nPr—Ph 1-2127 ring 12 4-F-2-nPr—Ph 1-2128 ring 13 4-F-2-nPr—Ph 1-2129 ring 14 4-F-2-nPr—Ph 1-2130 4-OH-cHex 4-F-2-nPr—Ph 1-2131 5-OH-dioxa 4-F-2-nPr—Ph 1-2132 5-OH-dithia 4-F-2-nPr—Ph 1-2133 5-OH-oxathia 4-F-2-nPr—Ph 1-2134 4-NHAc-cHex 4-F-2-nPr—Ph 1-2135 5-NHAc-dioxa 4-F-2-nPr—Ph 1-2136 5-NHAc-dithia 4-F-2-nPr—Ph 1-2137 5-NHAc-oxathia 4-F-2-nPr—Ph 1-2138 4,4-diMe-cHex 4-F-2-nPr—Ph 1-2139 5,5-diMe-dioxa 4-F-2-nPr—Ph 1-2140 5,5-diMe-dithia 4-F-2-nPr—Ph 1-2141 5,5-diMe-oxathia 4-F-2-nPr—Ph 1-2142 4,4-diHM-cHex 4-F-2-nPr—Ph 1-2143 5,5-diHM-dioxa 4-F-2-nPr—Ph 1-2144 5,5-diHM-dithia 4-F-2-nPr—Ph 1-2145 5,5-diHM-oxathia 4-F-2-nPr—Ph 1-2146 ring 15 4-F-2-nPr—Ph 1-2147 ring 16 4-F-2-nPr—Ph 1-2148 ring 17 4-F-2-nPr—Ph 1-2149 ring 18 4-F-2-nPr—Ph 1-2150 4,4-diCO₂Et-cHex 4-F-2-nPr—Ph 1-2151 5,5-diCO₂Et-dioxa 4-F-2-nPr—Ph 1-2152 5,5-diCO₂Et-dithia 4-F-2-nPr—Ph 1-2153 5,5-diCO₂Et-oxathia 4-F-2-nPr—Ph 1-2154 ring 19 2-Cl—Ph 1-2155 ring 20 2-Cl—Ph 1-2156 ring 21 2-Cl—Ph 1-2157 ring 19 2-Br—Ph 1-2158 ring 20 2-Br—Ph 1-2159 ring 21 2-Br—Ph 1-2160 ring 19 2-Cl-6-Me—Ph 1-2161 ring 20 2-Cl-6-Me—Ph 1-2162 ring 21 2-Cl-6-Me—Ph 1-2163 ring 19 2-Cl-4-F—Ph 1-2164 ring 20 2-Cl-4-F—Ph 1-2165 ring 21 2-Cl-4-F—Ph 1-2166 ring 19 2,4-diF 1-2167 ring 20 2,4-diF 1-2168 ring 21 2,4-diF 1-2169 ring 19 2-Br-4-F—Ph 1-2170 ring 20 2-Br-4-F—Ph 1-2171 ring 21 2-Br-4-F—Ph 1-2172 ring 19 2-nBu-4-F—Ph 1-2173 ring 20 2-nBu-4-F—Ph 1-2174 ring 21 2-nBu-4-F—Ph 1-2175 ring 19 2-nPent-Ph 1-2176 ring 20 2-nPent-Ph 1-2177 ring 21 2-nPent-Ph 1-2178 ring 19 4-F-2-nPent-Ph 1-2179 ring 20 4-F-2-nPent-Ph 1-2180 ring 21 4-F-2-nPent-Ph 1-2181 ring 19 2-nHex—Ph 1-2182 ring 20 2-nHex—Ph 1-2183 ring 21 2-nHex—Ph 1-2184 ring 19 4-F-2-nHex—Ph 1-2185 ring 20 4-F-2-nHex—Ph 1-2186 ring 21 4-F-2-nHex—Ph 1-2187 ring 19 2-nHept-Ph 1-2188 ring 20 2-nHept-Ph 1-2189 ring 21 2-nHept-Ph 1-2190 ring 19 4-F-2-nHept-Ph 1-2191 ring 20 4-F-2-nHept-Ph 1-2192 ring 21 4-F-2-nHept-Ph 1-2193 ring 19 2-nOct-Ph 1-2194 ring 20 2-nOct-Ph 1-2195 ring 21 2-nOct-Ph 1-2196 ring 19 4-F-2-nOct-Ph 1-2197 ring 20 4-F-2-nOct-Ph 1-2198 ring 21 4-F-2-nOct-Ph 1-2199 ring 19 Ph 1-2200 ring 20 Ph 1-2201 ring 21 Ph 1-2202 ring 19 4-F—Ph 1-2203 ring 20 4-F—Ph 1-2204 ring 21 4-F—Ph 1-2205 ring 19 2-Cl-4-Me—Ph 1-2206 ring 20 2-Cl-4-Me—Ph 1-2207 ring 21 2-Cl-4-Me—Ph 1-2208 ring 19 2-nBu—Ph 1-2209 ring 20 2-nBu—Ph 1-2210 ring 21 2-nBu—Ph 1-2211 ring 19 2-nPr—Ph 1-2212 ring 20 2-nPr—Ph 1-2213 ring 21 2-nPr—Ph 1-2214 ring 19 4-F-2-nPr—Ph 1-2215 ring 20 4-F-2-nPr—Ph 1-2216 ring 21 4-F-2-nPr—Ph 1-2217 dioxo 2-F—Ph 1-2218 4-HM-dioxo 2-F—Ph 1-2219 4,5-diHM-dioxo 2-F—Ph 1-2220 4,5-diHE-dioxo 2-F—Ph 1-2221 ring 19 2-F—Ph 1-2222 ring 20 2-F—Ph 1-2223 ring 21 2-F—Ph 1-2224 dioxo 2-I—Ph 1-2225 4-HM-dioxo 2-I—Ph 1-2226 4,5-diHM-dioxo 2-I—Ph 1-2227 4,5-diHE-dioxo 2-I—Ph 1-2228 ring 19 2-I—Ph 1-2229 ring 20 2-I—Ph 1-2230 ring 21 2-I—Ph 1-2231 dioxo 4-Cl—Ph 1-2232 4-HM-dioxo 4-Cl—Ph 1-2233 4,5-diHM-dioxo 4-Cl—Ph 1-2234 4,5-diHE-dioxo 4-Cl—Ph 1-2235 ring 19 4-Cl—Ph 1-2236 ring 20 4-Cl—Ph 1-2237 ring 21 4-Cl—Ph 1-2238 dioxo 2-Me—Ph 1-2239 4-HM-dioxo 2-Me—Ph 1-2240 4,5-diHM-dioxo 2-Me—Ph 1-2241 4,5-diHE-dioxo 2-Me—Ph 1-2242 ring 19 2-Me—Ph 1-2243 ring 20 2-Me—Ph 1-2244 ring 21 2-Me—Ph 1-2245 dioxo 2-Et—Ph 1-2246 4-HM-dioxo 2-Et—Ph 1-2247 4,5-diHM-dioxo 2-Et—Ph 1-2248 4,5-diHE-dioxo 2-Et—Ph 1-2249 ring 19 2-Et—Ph 1-2250 ring 20 2-Et—Ph 1-2251 ring 21 2-Et—Ph 1-2252 dioxo 2-C≡CH—Ph 1-2253 4-HM-dioxo 2-C≡CH—Ph 1-2254 4,5-diHM-dioxo 2-C≡CH—Ph 1-2255 4,5-diHE-dioxo 2-C≡CH—Ph 1-2256 ring 19 2-C≡CH—Ph 1-2257 ring 20 2-C≡CH—Ph 1-2258 ring 21 2-C≡CH—Ph 1-2259 dioxo 2-iPr—Ph 1-2260 4-HM-dioxo 2-iPr—Ph 1-2261 4,5-diHM-dioxo 2-iPr—Ph 1-2262 4,5-diHE-dioxo 2-iPr—Ph 1-2263 ring 19 2-iPr—Ph 1-2264 ring 20 2-iPr—Ph 1-2265 ring 21 2-iPr—Ph 1-2266 dioxo 2-tBu—Ph 1-2267 4-HM-dioxo 2-tBu—Ph 1-2268 4,5-diHM-dioxo 2-tBu—Ph 1-2269 4,5-diHE-dioxo 2-tBu—Ph 1-2270 ring 19 2-tBu—Ph 1-2271 ring 20 2-tBu—Ph 1-2272 ring 21 2-tBu—Ph 1-2273 dioxo 2-sBu—Ph 1-2274 4-HM-dioxo 2-sBu—Ph 1-2275 4,5-diHM-dioxo 2-sBu—Ph 1-2276 4,5-diHE-dioxo 2-sBu—Ph 1-2277 ring 19 2-sBu—Ph 1-2278 ring 20 2-sBu—Ph 1-2279 ring 21 2-sBu—Ph 1-2280 dioxo 2-OMe—Ph 1-2281 4-HM-dioxo 2-OMe—Ph 1-2282 4,5-diHM-dioxo 2-OMe—Ph 1-2283 4,5-diHE-dioxo 2-OMe—Ph 1-2284 ring 19 2-OMe—Ph 1-2285 ring 20 2-OMe—Ph 1-2286 ring 21 2-OMe—Ph 1-2287 dioxo 2-OEt—Ph 1-2288 4-HM-dioxo 2-OEt—Ph 1-2289 4,5-diHM-dioxo 2-OEt—Ph 1-2290 4,5-diHE-dioxo 2-OEt—Ph 1-2291 ring 19 2-OEt—Ph 1-2292 ring 20 2-OEt—Ph 1-2293 ring 21 2-OEt—Ph 1-2294 dioxo 2-OCHF₂—Ph 1-2295 4-HM-dioxo 2-OCHF₂—Ph 1-2296 4,5-diHM-dioxo 2-OCHF₂—Ph 1-2297 4,5-diHE-dioxo 2-OCHF₂—Ph 1-2298 ring 19 2-OCHF₂—Ph 1-2299 ring 20 2-OCHF₂—Ph 1-2300 ring 21 2-OCHF₂—Ph 1-2301 dioxo 2-SMe—Ph 1-2302 4-HM-dioxo 2-SMe—Ph 1-2303 4,5-diHM-dioxo 2-SMe—Ph 1-2304 4,5-diHE-dioxo 2-SMe—Ph 1-2305 ring 19 2-SMe—Ph 1-2306 ring 20 2-SMe—Ph 1-2307 ring 21 2-SMe—Ph 1-2308 dioxo 2-Ac—Ph 1-2309 4-HM-dioxo 2-Ac—Ph 1-2310 4,5-diHM-dioxo 2-Ac—Ph 1-2311 4,5-diHE-dioxo 2-Ac—Ph 1-2312 ring 19 2-Ac—Ph 1-2313 ring 20 2-Ac—Ph 1-2314 ring 21 2-Ac—Ph 1-2315 dioxo 2-Bn—Ph 1-2316 4-HM-dioxo 2-Bn—Ph 1-2317 4,5-diHM-dioxo 2-Bn—Ph 1-2318 4,5-diHE-dioxo 2-Bn—Ph 1-2319 ring 19 2-Bn—Ph 1-2320 ring 20 2-Bn—Ph 1-2321 ring 21 2-Bn—Ph 1-2322 dioxo 2-Mor-Ph 1-2323 4-HM-dioxo 2-Mor-Ph 1-2324 4,5-diHM-dioxo 2-Mor-Ph 1-2325 4,5-diHE-dioxo 2-Mor-Ph 1-2326 ring 19 2-Mor-Ph 1-2327 ring 20 2-Mor-Ph 1-2328 ring 21 2-Mor-Ph 1-2329 dioxo Flu 1-2330 4-HM-dioxo Flu 1-2331 4,5-diHM-dioxo Flu 1-2332 4,5-diHE-dioxo Flu 1-2333 ring 19 Flu 1-2334 ring 20 Flu 1-2335 ring 21 Flu 1-2336 dioxo 2-CH₂CH₂Pyrd-Ph 1-2337 4-HM-dioxo 2-CH₂CH₂Pyrd-Ph 1-2338 4,5-diHM-dioxo 2-CH₂CH₂Pyrd-Ph 1-2339 4,5-diHE-dioxo 2-CH₂CH₂Pyrd-Ph 1-2340 ring 19 2-CH₂CH₂Pyrd-Ph 1-2341 ring 20 2-CH₂CH₂Pyrd-Ph 1-2342 ring 21 2-CH₂CH₂Pyrd-Ph 1-2343 dioxo 2-CH₂CH₂NHBoc—Ph 1-2344 4-HM-dioxo 2-CH₂CH₂NHBoc—Ph 1-2345 4,5-diHM-dioxo 2-CH₂CH₂NHBoc—Ph 1-2346 4,5-diHE-dioxo 2-CH₂CH₂NHBoc—Ph 1-2347 ring 19 2-CH₂CH₂NHBoc—Ph 1-2348 ring 20 2-CH₂CH₂NHBoc—Ph 1-2349 ring 21 2-CH₂CH₂NHBoc—Ph 1-2350 dioxo 2-NH₂—Ph 1-2351 4-HM-dioxo 2-NH₂—Ph 1-2352 4,5-diHM-dioxo 2-NH₂—Ph 1-2353 4,5-diHE-dioxo 2-NH₂—Ph 1-2354 ring 19 2-NH₂—Ph 1-2355 ring 20 2-NH₂—Ph 1-2356 ring 21 2-NH₂—Ph 1-2357 dioxo 4-F-2-Me—Ph 1-2358 4-HM-dioxo 4-F-2-Me—Ph 1-2359 4,5-diHM-dioxo 4-F-2-Me—Ph 1-2360 4,5-diHE-dioxo 4-F-2-Me—Ph 1-2361 ring 19 4-F-2-Me—Ph 1-2362 ring 20 4-F-2-Me—Ph 1-2363 ring 21 4-F-2-Me—Ph 1-2364 dioxo 3-Cl-4-F—Ph 1-2365 4-HM-dioxo 3-Cl-4-F—Ph 1-2366 4,5-diHM-dioxo 3-Cl-4-F—Ph 1-2367 4,5-diHE-dioxo 3-Cl-4-F—Ph 1-2368 ring 19 3-Cl-4-F—Ph 1-2369 ring 20 3-Cl-4-F—Ph 1-2370 ring 21 3-Cl-4-F—Ph 1-2371 dioxo 4-F-3-CF₃—Ph 1-2372 4-HM-dioxo 4-F-3-CF₃—Ph 1-2373 4,5-diHM-dioxo 4-F-3-CF₃—Ph 1-2374 4,5-diHE-dioxo 4-F-3-CF₃—Ph 1-2375 ring 19 4-F-3-CF₃—Ph 1-2376 ring 20 4-F-3-CF₃—Ph 1-2377 ring 21 4-F-3-CF₃—Ph 1-2378 dioxo 4-F-3-OMe—Ph 1-2379 4-HM-dioxo 4-F-3-OMe—Ph 1-2380 4,5-diHM-dioxo 4-F-3-OMe—Ph 1-2381 4,5-diHE-dioxo 4-F-3-OMe—Ph 1-2382 ring 19 4-F-3-OMe—Ph 1-2383 ring 20 4-F-3-OMe—Ph 1-2384 ring 21 4-F-3-OMe—Ph 1-2385 dioxo 3,4-diF—Ph 1-2386 4-HM-dioxo 3,4-diF—Ph 1-2387 4,5-diHM-dioxo 3,4-diF—Ph 1-2388 4,5-diHE-dioxo 3,4-diF—Ph 1-2389 ring 19 3,4-diF—Ph 1-2390 ring 20 3,4-diF—Ph 1-2391 ring 21 3,4-diF—Ph 1-2392 dioxo 2,4-diOMe—Ph 1-2393 4-HM-dioxo 2,4-diOMe—Ph 1-2394 4,5-diHM-dioxo 2,4-diOMe—Ph 1-2395 4,5-diHE-dioxo 2,4-diOMe—Ph 1-2396 ring 19 2,4-diOMe—Ph 1-2397 ring 20 2,4-diOMe—Ph 1-2398 ring 21 2,4-diOMe—Ph 1-2399 dioxo 4-Cl-2-F—Ph 1-2400 4-HM-dioxo 4-Cl-2-F—Ph 1-2401 4,5-diHM-dioxo 4-Cl-2-F—Ph 1-2402 4,5-diHE-dioxo 4-Cl-2-F—Ph 1-2403 ring 19 4-Cl-2-F—Ph 1-2404 ring 20 4-Cl-2-F—Ph 1-2405 ring 21 4-Cl-2-F—Ph 1-2406 dioxo 2-Br-4-Cl—Ph 1-2407 4-HM-dioxo 2-Br-4-Cl—Ph 1-2408 4,5-diHM-dioxo 2-Br-4-Cl—Ph 1-2409 4,5-diHE-dioxo 2-Br-4-Cl—Ph 1-2410 ring 19 2-Br-4-Cl—Ph 1-2411 ring 20 2-Br-4-Cl—Ph 1-2412 ring 21 2-Br-4-Cl—Ph 1-2413 dioxo 4-Cl-2-Me—Ph 1-2414 4-HM-dioxo 4-Cl-2-Me—Ph 1-2415 4,5-diHM-dioxo 4-Cl-2-Me—Ph 1-2416 4,5-diHE-dioxo 4-Cl-2-Me—Ph 1-2417 ring 19 4-Cl-2-Me—Ph 1-2418 ring 20 4-Cl-2-Me—Ph 1-2419 ring 21 4-Cl-2-Me—Ph 1-2420 dioxo 4-Cl-2-CO₂Me—Ph 1-2421 4-HM-dioxo 4-Cl-2-CO₂Me—Ph 1-2422 4,5-diHM-dioxo 4-Cl-2-CO₂Me—Ph 1-2423 4,5-diHE-dioxo 4-Cl-2-CO₂Me—Ph 1-2424 ring 19 4-Cl-2-CO₂Me—Ph 1-2425 ring 20 4-Cl-2-CO₂Me—Ph 1-2426 ring 21 4-Cl-2-CO₂Me—Ph 1-2427 dioxo 3,4-diCl—Ph 1-2428 4-HM-dioxo 3,4-diCl—Ph 1-2429 4,5-diHM-dioxo 3,4-diCl—Ph 1-2430 4,5-diHE-dioxo 3,4-diCl—Ph 1-2431 ring 19 3,4-diCl—Ph 1-2432 ring 20 3,4-diCl—Ph 1-2433 ring 21 3,4-diCl—Ph 1-2434 dioxo 2,5-diF—Ph 1-2435 4-HM-dioxo 2,5-diF—Ph 1-2436 4,5-diHM-dioxo 2,5-diF—Ph 1-2437 4,5-diHE-dioxo 2,5-diF—Ph 1-2438 ring 19 2,5-diF—Ph 1-2439 ring 20 2,5-diF—Ph 1-2440 ring 21 2,5-diF—Ph 1-2441 dioxo 2,6-diF—Ph 1-2442 4-HM-dioxo 2,6-diF—Ph 1-2443 4,5-diHM-dioxo 2,6-diF—Ph 1-2444 4,5-diHE-dioxo 2,6-diF—Ph 1-2445 ring 19 2,6-diF—Ph 1-2446 ring 20 2,6-diF—Ph 1-2447 ring 21 2,6-diF—Ph 1-2448 dioxo 2-F-4-Me—Ph 1-2449 4-HM-dioxo 2-F-4-Me—Ph 1-2450 4,5-diHM-dioxo 2-F-4-Me—Ph 1-2451 4,5-diHE-dioxo 2-F-4-Me—Ph 1-2452 ring 19 2-F-4-Me—Ph 1-2453 ring 20 2-F-4-Me—Ph 1-2454 ring 21 2-F-4-Me—Ph 1-2455 dioxo 2-F-5-Me—Ph 1-2456 4-HM-dioxo 2-F-5-Me—Ph 1-2457 4,5-diHM-dioxo 2-F-5-Me—Ph 1-2458 4,5-diHE-dioxo 2-F-5-Me—Ph 1-2459 ring 19 2-F-5-Me—Ph 1-2460 ring 20 2-F-5-Me—Ph 1-2461 ring 21 2-F-5-Me—Ph 1-2462 dioxo 2-F-4-OMe—Ph 1-2463 4-HM-dioxo 2-F-4-OMe—Ph 1-2464 4,5-diHM-dioxo 2-F-4-OMe—Ph 1-2465 4,5-diHE-dioxo 2-F-4-OMe—Ph 1-2466 ring 19 2-F-4-OMe—Ph 1-2467 ring 20 2-F-4-OMe—Ph 1-2468 ring 21 2-F-4-OMe—Ph 1-2469 dioxo 5-Cl-2-F—Ph 1-2470 4-HM-dioxo 5-Cl-2-F—Ph 1-2471 4,5-diHM-dioxo 5-Cl-2-F—Ph 1-2472 4,5-diHE-dioxo 5-Cl-2-F—Ph 1-2473 ring 19 5-Cl-2-F—Ph 1-2474 ring 20 5-Cl-2-F—Ph 1-2475 ring 21 5-Cl-2-F—Ph 1-2476 dioxo 2,3,4-triF—Ph 1-2477 4-HM-dioxo 2,3,4-triF—Ph 1-2478 4,5-diHM-dioxo 2,3,4-triF—Ph 1-2479 4,5-diHE-dioxo 2,3,4-triF—Ph 1-2480 ring 19 2,3,4-triF—Ph 1-2481 ring 20 2,3,4-triF—Ph 1-2482 ring 21 2,3,4-triF—Ph 1-2483 dioxo 2,4,5-triF—Ph 1-2484 4-HM-dioxo 2,4,5-triF—Ph 1-2485 4,5-diHM-dioxo 2,4,5-triF—Ph 1-2486 4,5-diHE-dioxo 2,4,5-triF—Ph 1-2487 ring 19 2,4,5-triF—Ph 1-2488 ring 20 2,4,5-triF—Ph 1-2489 ring 21 2,4,5-triF—Ph 1-2490 dioxo 2,4,6-triF—Ph 1-2491 4-HM-dioxo 2,4,6-triF—Ph 1-2492 4,5-diHM-dioxo 2,4,6-triF—Ph 1-2493 4,5-diHE-dioxo 2,4,6-triF—Ph 1-2494 ring 19 2,4,6-triF—Ph 1-2495 ring 20 2,4,6-triF—Ph 1-2496 ring 21 2,4,6-triF—Ph 1-2497 dioxo 2,4-diCl—Ph 1-2498 4-HM-dioxo 2,4-diCl—Ph 1-2499 4,5-diHM-dioxo 2,4-diCl—Ph 1-2500 4,5-diHE-dioxo 2,4-diCl—Ph 1-2501 ring 19 2,4-diCl—Ph 1-2502 ring 20 2,4-diCl—Ph 1-2503 ring 21 2,4-diCl—Ph 1-2504 dioxo 4-Br-2-Cl—Ph 1-2505 4-HM-dioxo 4-Br-2-Cl—Ph 1-2506 4,5-diHM-dioxo 4-Br-2-Cl—Ph 1-2507 4,5-diHE-dioxo 4-Br-2-Cl—Ph 1-2508 ring 19 4-Br-2-Cl—Ph 1-2509 ring 20 4-Br-2-Cl—Ph 1-2510 ring 21 4-Br-2-Cl—Ph 1-2511 dioxo 4-tBu-2-Cl—Ph 1-2512 4-HM-dioxo 4-tBu-2-Cl—Ph 1-2513 4,5-diHM-dioxo 4-tBu-2-Cl—Ph 1-2514 4,5-diHE-dioxo 4-tBu-2-Cl—Ph 1-2515 ring 19 4-tBu-2-Cl—Ph 1-2516 ring 20 4-tBu-2-Cl—Ph 1-2517 ring 21 4-tBu-2-Cl—Ph 1-2518 dioxo 2-Cl-6-F—Ph 1-2519 4-HM-dioxo 2-Cl-6-F—Ph 1-2520 4,5-diHM-dioxo 2-Cl-6-F—Ph 1-2521 4,5-diHE-dioxo 2-Cl-6-F—Ph 1-2522 ring 19 2-Cl-6-F—Ph 1-2523 ring 20 2-Cl-6-F—Ph 1-2524 ring 21 2-Cl-6-F—Ph 1-2525 dioxo 2,6-diCl—Ph 1-2526 4-HM-dioxo 2,6-diCl—Ph 1-2527 4,5-diHM-dioxo 2,6-diCl—Ph 1-2528 4,5-diHE-dioxo 2,6-diCl—Ph 1-2529 ring 19 2,6-diCl—Ph 1-2530 ring 20 2,6-diCl—Ph 1-2531 ring 21 2,6-diCl—Ph 1-2532 dioxo 2,3-diCl—Ph 1-2533 4-HM-dioxo 2,3-diCl—Ph 1-2534 4,5-diHM-dioxo 2,3-diCl—Ph 1-2535 4,5-diHE-dioxo 2,3-diCl—Ph 1-2536 ring 19 2,3-diCl—Ph 1-2537 ring 20 2,3-diCl—Ph 1-2538 ring 21 2,3-diCl—Ph 1-2539 dioxo 2,5-diCl—Ph 1-2540 4-HM-dioxo 2,5-diCl—Ph 1-2541 4,5-diHM-dioxo 2,5-diCl—Ph 1-2542 4,5-diHE-dioxo 2,5-diCl—Ph 1-2543 ring 19 2,5-diCl—Ph 1-2544 ring 20 2,5-diCl—Ph 1-2545 ring 21 2,5-diCl—Ph 1-2546 dioxo 2-Cl-4,6-diF—Ph 1-2547 4-HM-dioxo 2-Cl-4,6-diF—Ph 1-2548 4,5-diHM-dioxo 2-Cl-4,6-diF—Ph 1-2549 4,5-diHE-dioxo 2-Cl-4,6-diF—Ph 1-2550 ring 19 2-Cl-4,6-diF—Ph 1-2551 ring 20 2-Cl-4,6-diF—Ph 1-2552 ring 21 2-Cl-4,6-diF—Ph 1-2553 dioxo 2,6-diCl-4-F—Ph 1-2554 4-HM-dioxo 2,6-diCl-4-F—Ph 1-2555 4,5-diHM-dioxo 2,6-diCl-4-F—Ph 1-2556 4,5-diHE-dioxo 2,6-diCl-4-F—Ph 1-2557 ring 19 2,6-diCl-4-F—Ph 1-2558 ring 20 2,6-diCl-4-F—Ph 1-2559 ring 21 2,6-diCl-4-F—Ph 1-2560 dioxo 2-Br-6-Cl-4-F—Ph 1-2561 4-HM-dioxo 2-Br-6-Cl-4-F—Ph 1-2562 4,5-diHM-dioxo 2-Br-6-Cl-4-F—Ph 1-2563 4,5-diHE-dioxo 2-Br-6-Cl-4-F—Ph 1-2564 ring 19 2-Br-6-Cl-4-F—Ph 1-2565 ring 20 2-Br-6-Cl-4-F—Ph 1-2566 ring 21 2-Br-6-Cl-4-F—Ph 1-2567 dioxo 4-Cl-2-OMe-5-Me—Ph 1-2568 4-HM-dioxo 4-Cl-2-OMe-5-Me—Ph 1-2569 4,5-diHM-dioxo 4-Cl-2-OMe-5-Me—Ph 1-2570 4,5-diHE-dioxo 4-Cl-2-OMe-5-Me—Ph 1-2571 ring 19 4-Cl-2-OMe-5-Me—Ph 1-2572 ring 20 4-Cl-2-OMe-5-Me—Ph 1-2573 ring 21 4-Cl-2-OMe-5-Me—Ph 1-2574 dioxo 2,4-diBr—Ph 1-2575 4-HM-dioxo 2,4-diBr—Ph 1-2576 4,5-diHM-dioxo 2,4-diBr—Ph 1-2577 4,5-diHE-dioxo 2,4-diBr—Ph 1-2578 ring 19 2,4-diBr—Ph 1-2579 ring 20 2,4-diBr—Ph 1-2580 ring 21 2,4-diBr—Ph 1-2581 dioxo 2,6-diBr—Ph 1-2582 4-HM-dioxo 2,6-diBr—Ph 1-2583 4,5-diHM-dioxo 2,6-diBr—Ph 1-2584 4,5-diHE-dioxo 2,6-diBr—Ph 1-2585 ring 19 2,6-diBr—Ph 1-2586 ring 20 2,6-diBr—Ph 1-2587 ring 21 2,6-diBr—Ph 1-2588 dioxo 2-Br-4-iPr—Ph 1-2589 4-HM-dioxo 2-Br-4-iPr—Ph 1-2590 4,5-diHM-dioxo 2-Br-4-iPr—Ph 1-2591 4,5-diHE-dioxo 2-Br-4-iPr—Ph 1-2592 ring 19 2-Br-4-iPr—Ph 1-2593 ring 20 2-Br-4-iPr—Ph 1-2594 ring 21 2-Br-4-iPr—Ph 1-2595 dioxo 2-nNon-Ph 1-2596 4-HM-dioxo 2-nNon-Ph 1-2597 4,5-diHM-dioxo 2-nNon-Ph 1-2598 4,5-diHE-dioxo 2-nNon-Ph 1-2599 ring 19 2-nNon-Ph 1-2600 ring 20 2-nNon-Ph 1-2601 ring 21 2-nNon-Ph 1-2602 dioxo 4-F-2-nNon-Ph 1-2603 4-HM-dioxo 4-F-2-nNon-Ph 1-2604 4,5-diHM-dioxo 4-F-2-nNon-Ph 1-2605 4,5-diHE-dioxo 4-F-2-nNon-Ph 1-2606 ring 19 4-F-2-nNon-Ph 1-2607 ring 20 4-F-2-nNon-Ph 1-2608 ring 21 4-F-2-nNon-Ph 1-2609 dioxo 2-nDec-Ph 1-2610 4-HM-dioxo 2-nDec-Ph 1-2611 4,5-diHM-dioxo 2-nDec-Ph 1-2612 4,5-diHE-dioxo 2-nDec-Ph 1-2613 ring 19 2-nDec-Ph 1-2614 ring 20 2-nDec-Ph 1-2615 ring 21 2-nDec-Ph 1-2616 dioxo 4-F-2-nDec-Ph 1-2617 4-HM-dioxo 4-F-2-nDec-Ph 1-2618 4,5-diHM-dioxo 4-F-2-nDec-Ph 1-2619 4,5-diHE-dioxo 4-F-2-nDec-Ph 1-2620 ring 19 4-F-2-nDec-Ph 1-2621 ring 20 4-F-2-nDec-Ph 1-2622 ring 21 4-F-2-nDec-Ph 1-2623 dioxo 2-Et-4-F—Ph 1-2624 4-HM-dioxo 2-Et-4-F—Ph 1-2625 4,5-diHM-dioxo 2-Et-4-F—Ph 1-2626 4,5-diHE-dioxo 2-Et-4-F—Ph 1-2627 ring 19 2-Et-4-F—Ph 1-2628 ring 20 2-Et-4-F—Ph 1-2629 ring 21 2-Et-4-F—Ph

TABLE 2

Compound No. X, Y R³ 2-1 dioxo 2-Cl—Ph 2-2 4-HM-dioxo 2-Cl—Ph 2-3 4,5 -diHM-dioxo 2-Cl—Ph 2-4 4,5 -diHE-dioxo 2-Cl—Ph 2-5 dioxo 2-Br—Ph 2-6 4-HM-dioxo 2-Br—Ph 2-7 4,5 -diHM-dioxo 2-Br—Ph 2-8 4,5-diHE-dioxo 2-Br—Ph 2-9 dioxo 2-Cl-6-Me—Ph 2-10 4-HM-dioxo 2-Cl-6-Me—Ph 2-11 4,5-diHM-dioxo 2-Cl-6-Me—Ph 2-12 4,5-diHE-dioxo 2-Cl-6-Me—Ph 2-13 dioxo 2-Cl-4-F—Ph 2-14 4-HM-dioxo 2-Cl-4-F—Ph 2-15 4,5-diHM-dioxo 2-Cl-4-F—Ph 2-16 4,5-diHE-dioxo 2-Cl-4-F—Ph 2-17 dioxo 2,4-diF 2-18 4-HM-dioxo 2,4-diF 2-19 4,5-diHM-dioxo 2,4-diF 2-20 4,5-diHE-dioxo 2,4-diF 2-21 dioxo 2-Br-4-F Ph 2-22 4-HM-dioxo 2-Br-4-F Ph 2-23 4,5-diHM-dioxo 2-Br-4-F Ph 2-24 4,5-diHE-dioxo 2-Br-4-F Ph 2-25 dioxo 2-nBu-4-F Ph 2-26 4-HM-dioxo 2-nBu-4-F Ph 2-27 4,5-diHM-dioxo 2-nBu-4-F Ph 2-28 4,5-diHE-dioxo 2-nBu-4-F Ph 2-29 dioxo 2-nPent-Ph 2-30 4-HM-dioxo 2-nPent-Ph 2-31 4,5-diHM-dioxo 2-nPent-Ph 2-32 4,5-diHE-dioxo 2-nPent-Ph 2-33 dioxo 4-F-2-nPent-Ph 2-34 4-HM-dioxo 4-F-2-nPent-Ph 2-35 4,5-diHM-dioxo 4-F-2-nPent-Ph 2-35 4,5-diHE-dioxo 4-F-2-nPent-Ph 2-37 dioxo 2-nHex—Ph 2-38 4-HM-dioxo 2-nHex—Ph 2-39 4,5-diHM-dioxo 2-nHex—Ph 2-40 4,5-diHE-dioxo 2-nHex—Ph 2-41 dioxo 4-F-2-nHex Ph 2-42 4-HM-dioxo 4-F-2-nHex Ph 2-43 4,5-diHM-dioxo 4-F-2-nHex Ph 2-44 4,5-diHE-dioxo 4-F-2-nHex Ph 2-45 dioxo 2-nHept-Ph 2-46 4-HM-dioxo 2-nHept-Ph 2-47 4,5-diHM-dioxo 2-nHept-Ph 2-48 4,5-diHE-dioxo 2-nHept-Ph 2-49 dioxo 4-F-2-nHept-Ph 2-50 4-HM-dioxo 4-F-2-nHept-Ph 2-51 4,5-diHM-dioxo 4-F-2-nHept-Ph 2-52 4,5-diHE-dioxo 4-F-2-nHept-Ph 2-53 dioxo 2-nOct-Ph 2-54 4-HM-dioxo 2-nOct-Ph 2-55 4,5-diHM-dioxo 2-nOct-Ph 2-56 4,5-diHE-dioxo 2-nOct-Ph 2-57 dioxo 4-F-2-nOct-Ph 2-58 4-HM-dioxo 4-F-2-nOct-Ph 2-59 4,5-diHM-dioxo 4-F-2-nOct-Ph 2-60 4,5-diHE-dioxo 4-F-2-nOct-Ph 2-61 dioxo Ph 2-62 4-HM-dioxo Ph 2-63 4,5-diHM-dioxo Ph 2-64 4,5-diHE-dioxo Ph 2-65 dioxo 4-F—Ph 2-66 4-HM-dioxo 4-F—Ph 2-67 4,5-diHM-dioxo 4-F—Ph 2-68 4,5-diHE-dioxo 4-F—Ph 2-69 dioxo 2-Cl-4-Me Ph 2-70 4-HM-dioxo 2-Cl-4-Me Ph 2-71 4,5-diHM-dioxo 2-Cl-4-Me Ph 2-72 4,5-diHE-dioxo 2-Cl-4-Me Ph 2-73 dioxo 2-nBu—Ph 2-74 4-HM-dioxo 2-nBu—Ph 2-75 4,5-diHM-dioxo 2-nBu—Ph 2-76 4,5-diHE-dioxo 2-nBu—Ph 2-77 dioxo 2-nPr—Ph 2-78 4-HM-dioxo 2-nPr—Ph 2-79 4,5-diHM-dioxo 2-nPr—Ph 2-80 4,5-diHE-dioxo 2-nPr—Ph 2-81 dioxo 4-F-2-nPr—Ph 2-82 4-HM-dioxo 4-F-2-nPr—Ph 2-83 4,5-diHM-dioxo 4-F-2-nPr—Ph 2-84 4,5-diHE-dioxo 4-F-2-nPr—Ph

TABLE 3

Compound No. X, Y R² R³ 3-1 dioxo Me 2-Cl—Ph 3-2 4-HM-dioxo Me 2-Cl—Ph 3-3 4,5-diHM-dioxo Me 2-Cl—Ph 3-4 4,5-diHE-dioxo Me 2-Cl—Ph 3-5 dioxo nPr 2-Cl—Ph 3-6 4-HM-dioxo nPr 2-Cl—Ph 3-7 4,5-diHM-dioxo nPr 2-Cl—Ph 3-8 4,5-diHE-dioxo nPr 2-Cl—Ph 3-9 dioxo nBu 2-Cl—Ph 3-10 4-HM-dioxo nBu 2-Cl—Ph 3-11 4,5-diHM-dioxo nBu 2-Cl—Ph 3-12 4,5-diHE-dioxo nBu 2-Cl—Ph 3-13 dioxo iPr 2-Cl—Ph 3-14 4-HM-dioxo iPr 2-Cl—Ph 3-15 4,5-diHM-dioxo iPr 2-Cl—Ph 3-16 4,5-diHE-dioxo iPr 2-Cl—Ph 3-17 dioxo tBu 2-Cl—Ph 3-18 4-HM-dioxo tBu 2-Cl—Ph 3-19 4,5-diHM-dioxo tBu 2-Cl—Ph 3-20 4,5-diHE-dioxo tBu 2-Cl—Ph 3-21 dioxo CH₂OAc 2-Cl—Ph 3-22 4-HM-dioxo CH₂OAc 2-Cl—Ph 3-23 4,5-diHM-dioxo CH₂OAc 2-Cl—Ph 3-24 4,5-diHE-dioxo CH₂OAc 2-Cl—Ph 3-25 dioxo Me 2-Br—Ph 3-26 4-HM-dioxo Me 2-Br—Ph 3-27 4,5-diHM-dioxo Me 2-Br—Ph 3-28 4,5-diHE-dioxo Me 2-Br—Ph 3-29 dioxo nPr 2-Br—Ph 3-30 4-HM-dioxo nPr 2-Br—Ph 3-31 4,5-diHM-dioxo nPr 2-Br—Ph 3-32 4,5-diHE-dioxo nPr 2-Br—Ph 3-33 dioxo nBu 2-Br—Ph 3-34 4-HM-dioxo nBu 2-Br—Ph 3-35 4,5-diHM-dioxo nBu 2-Br—Ph 3-36 4,5-diHE-dioxo nBu 2-Br—Ph 3-37 dioxo iPr 2-Br—Ph 3-38 4-HM-dioxo iPr 2-Br—Ph 3-39 4,5-diHM-dioxo iPr 2-Br—Ph 3-40 4,5-diHE-d oxo iPr 2-Br—Ph 3-41 dioxo tBu 2-Br—Ph 3-42 4-HM-dioxo tBu 2-Br—Ph 3-43 4,5-diHM-dioxo tBu 2-Br—Ph 3-44 4,5-diHE-dioxo tBu 2-Br—Ph 3-45 dioxo CH₂OAc 2-Br—Ph 3-45 4-HM-dioxo CH₂OAc 2-Br—Ph 3-47 4,5-diHM-dioxo CH₂OAc 2-Br—Ph 3-48 4,5-diHE-dioxo CH₂OAc 2-Br—Ph 3-49 dioxo Me 2-Cl-6-Me—Ph 3-50 4-HM-dioxo Me 2-Cl-6-Me—Ph 3-51 4,5-diHM-dioxo Me 2-Cl-6-Me—Ph 3-52 4,5-diHE-dioxo Me 2-Cl-6-Me—Ph 3-53 dioxo nPr 2-Cl-6-Me—Ph 3-54 4-HM-dioxo nPr 2-Cl-6-Me—Ph 3-55 4,5-diHM-dioxo nPr 2-Cl-6-Me—Ph 3-56 4,5-diHE-dioxo nPr 2-Cl-6-Me—Ph 3-57 dioxo nBu 2-Cl-6-Me—Ph 3-58 4-HM-dioxo nBu 2-Cl-6-Me—Ph 3-59 4,5-diHM-dioxo nBu 2-Cl-6-Me—Ph 3-60 4,5-diHE-dioxo nBu 2-Cl-6-Me—Ph 3-61 dioxo iPr 2-Cl-6-Me—Ph 3-62 4-HM-dioxo iPr 2-Cl-6-Me—Ph 3-63 4,5-diHM-dioxo iPr 2-Cl-6-Me—Ph 3-64 4,5-diHE-dioxo iPr 2-Cl-6-Me—Ph 3-65 dioxo tBu 2-Cl-6-Me—Ph 3-66 4-HM-dioxo tBu 2-Cl-6-Me—Ph 3-67 4,5-diHM-dioxo tBu 2-Cl-6-Me—Ph 3-68 4,5-diHE-dioxo tBu 2-Cl-6-Me—Ph 3-69 dioxo CH₂OAc 2-Cl-6-Me—Ph 3-70 4-HM-dioxo CH₂OAc 2-Cl-6-Me—Ph 3-71 4,5-diHM-dioxo CH₂OAc 2-Cl-6-Me—Ph 3-72 4,5-diHE-dioxo CH₂OAc 2-Cl-6-Me—Ph 3-73 dioxo Me 2-Cl-4-F—Ph 3-74 4-HM-dioxo Me 2-Cl-4-F—Ph 3-75 4,5-diHM-dioxo Me 2-Cl-4-F—Ph 3-76 4,5-diHE-dioxo Me 2-Cl-4-F—Ph 3-77 dioxo nPr 2-Cl-4-F—Ph 3-78 4-HM-dioxo nPr 2-Cl-4-F—Ph 3-79 4,5-diHM-dioxo nPr 2-Cl-4-F—Ph 3-80 4,5-diHE-dioxo nPr 2-Cl-4-F—Ph 3-81 dioxo nBu 2-Cl-4-F—Ph 3-82 4-HM-dioxo nBu 2-Cl-4-F—Ph 3-83 4,5-diHM-dioxo nBu 2-Cl-4-F—Ph 3-84 4,5-diHE-dioxo nBu 2-Cl-4-F—Ph 3-85 dioxo iPr 2-Cl-4-F—Ph 3-86 4-HM-dioxo iPr 2-Cl-4-F—Ph 3-87 4,5-diHM-dioxo iPr 2-Cl-4-F—Ph 3-88 4,5-diHE-dioxo iPr 2-Cl-4-F—Ph 3-89 dioxo tBu 2-Cl-4-F—Ph 3-90 4-HM-dioxo tBu 2-Cl-4-F—Ph 3-91 4,5-diHM-dioxo tBu 2-Cl-4-F—Ph 3-92 4,5-diHE-dioxo tBu 2-Cl-4-F—Ph 3-93 dioxo CH₂OAc 2-Cl-4-F—Ph 3-94 4-HM-dioxo CH₂OAc 2-Cl-4-F—Ph 3-95 4,5-diHM-dioxo CH₂OAc 2-Cl-4-F—Ph 3-96 4,5-diHE-dioxo CH₂OAc 2-Cl-4-F—Ph 3-97 dioxo Me 2,4-diF—Ph 3-98 4-HM-dioxo Me 2,4-diF—Ph 3-99 4,5-diHM-dioxo Me 2,4-diF—Ph 3-100 4,5-diHE-dioxo Me 2,4-diF—Ph 3-101 dioxo nPr 2,4-diF—Ph 3-102 4-HM-dioxo nPr 2,4-diF—Ph 3-103 4,5-diHM-dioxo nPr 2,4-diF—Ph 3-104 4,5-diHE-dioxo nPr 2,4-diF—Ph 3-105 dioxo nBu 2,4-diF—Ph 3-106 4-HM-dioxo nBu 2,4-diF—Ph 3-107 4,5-diHM-dioxo nBu 2,4-diF—Ph 3-108 4,5-diHE-dioxo nBu 2,4-diF—Ph 3-109 dioxo iPr 2,4-diF—Ph 3-110 4-HM-dioxo iPr 2,4-diF—Ph 3-111 4,5-diHM-dioxo iPr 2,4-diF—Ph 3-112 4,5-diHE-dioxo iPr 2,4-diF—Ph 3-113 dioxo tBu 2,4-diF—Ph 3-114 4-HM-dioxo tBu 2,4-diF—Ph 3-115 4,5-diHM-dioxo tBu 2,4-diF—Ph 3-116 4,5-diHE-dioxo tBu 2,4-diF—Ph 3-117 dioxo CH₂OAc 2,4-diF—Ph 3-118 4-HM-dioxo CH₂OAc 2,4-diF—Ph 3-119 4,5-diHM-dioxo CH₂OAc 2,4-diF—Ph 3-120 4,5-diHE-dioxo CH₂OAc 2,4-diF—Ph 3-121 dioxo Me 2-Br-4-F—Ph 3-122 4-HM-dioxo Me 2-Br-4-F—Ph 3-123 4,5-diHM-dioxo Me 2-Br-4-F—Ph 3-124 4,5-diHE-dioxo Me 2-Br-4-F—Ph 3-125 dioxo nPr 2-Br-4-F—Ph 3-126 4-HM-dioxo nPr 2-Br-4-F—Ph 3-127 4,5-diHM-dioxo nPr 2-Br-4-F—Ph 3-128 4,5-diHE-dioxo nPr 2-Br-4-F—Ph 3-129 dioxo nBu 2-Br-4-F—Ph 3-130 4-HM-dioxo nBu 2-Br-4-F—Ph 3-131 4,5-diHM-dioxo nBu 2-Br-4-F—Ph 3-132 4,5-diHE-dioxo nBu 2-Br-4-F—Ph 3-133 dioxo iPr 2-Br-4-F—Ph 3-134 4-HM-dioxo iPr 2-Br-4-F—Ph 3-135 4,5-diHM-dioxo iPr 2-Br-4-F—Ph 3-136 4,5-diHE-dioxo iPr 2-Br-4-F—Ph 3-137 dioxo tBu 2-Br-4-F—Ph 3-138 4-IIM-dioxo tBu 2-Br-4-F—Ph 3-139 4,5-diHM-dioxo tBu 2-Br-4-F—Ph 3-140 4,5-diHE-dioxo tBu 2-Br-4-F—Ph 3-141 dioxo CH₂OAc 2-Br-4-F—Ph 3-142 4-HM-dioxo CH₂OAc 2-Br-4-F—Ph 3-143 4,5-diHM-dioxo CH₂OAc 2-Br-4-F—Ph 3-144 4,5-diHE-dioxo CH₂OAc 2-Br-4-F—Ph 3-145 dioxo Me 2-nBu-4-F—Ph 3-146 4-HM-dioxo Me 2-nBu-4-F—Ph 3-147 4,5-diHM-dioxo Me 2-nBu-4-F—Ph 3-148 4,5-diHE-dioxo Me 2-nBu-4-F—Ph 3-149 dioxo nPr 2-nBu-4-F—Ph 3-150 4-HM-dioxo nPr 2-nBu-4-F—Ph 3-151 4,5-diHM-dioxo nPr 2-nBu-4-F—Ph 3-152 4,5-diHE-dioxo nPr 2-nBu-4-F—Ph 3-153 dioxo nBu 2-nBu-4-F—Ph 3-154 4-HM-dioxo nBu 2-nBu-4-F—Ph 3-155 4,5-diHM-dioxo nBu 2-nBu-4-F—Ph 3-156 4,5-diHE-dioxo nBu 2-nBu-4-F—Ph 3-157 dioxo iPr 2-nBu-4-F—Ph 3-158 4-HM-dioxo iPr 2-nBu-4-F—Ph 3-159 4,5-diHM-dioxo iPr 2-nBu-4-F—Ph 3-160 4,5-diHE-dioxo iPr 2-nBu-4-F—Ph 3-161 dioxo tBu 2-nBu-4-F—Ph 3-162 4-HM-dioxo tBu 2-nBu-4-F—Ph 3-163 4,5-diHM-dioxo tBu 2-nBu-4-F—Ph 3-164 4,5-diHE-dioxo tBu 2-nBu-4-F—Ph 3-165 dioxo CH₂OAc 2-nBu-4-F—Ph 3-166 4-HM-dioxo CH2OAo 2-nBu-4-F—Ph 3-167 4,5-diHM-dioxo CH₂OAc 2-nBu-4-F—Ph 3-168 4,5-diHE-dioxo CH₂OAc 2-nBu-4-F—Ph 3-169 dioxo Me 2-nPent-Ph 3-170 4-HM-dioxo Me 2-nPent-Ph 3-171 4,5-diHM-dioxo Me 2-nPent-Ph 3-172 4,5-diHE-dioxo Me 2-nPent-Ph 3-173 dioxo nPr 2-nPent-Ph 3-174 4-HM-dioxo nPr 2-nPent-Ph 3-175 4,5-diHM-dioxo nPr 2-nPent-Ph 3-176 4,5-diHE-dioxo nPr 2-nPent-Ph 3-177 dioxo nBu 2-nPent-Ph 3-178 4-HM-dioxo nBu 2-nPent-Ph 3-179 4,5-diHM-dioxo nBu 2-nPent-Ph 3-180 4,5-diHE-dioxo nBu 2-nPent-Ph 3-181 dioxo iPr 2-nPent-Ph 3-182 4-HM-dioxo iPr 2-nPent-Ph 3-183 4,5-diHM-dioxo iPr 2-nPent-Ph 3-184 4,5-diHE-dioxo iPr 2-nPent-Ph 3-185 dioxo tBu 2-nPent-Ph 3-186 4-HM-dioxo tBu 2-nPent-Ph 3-187 4,5-diHM-dioxo tBu 2-nPent-Ph 3-188 4,5-diHE-dioxo tBu 2-nPent-Ph 3-189 dioxo CH₂OAc 2-nPent-Ph 3-190 4-HM-dioxo CH₂OAc 2-nPent-Ph 3-191 4,5-diHM-dioxo CH₂OAc 2-nPent-Ph 3-192 4,5-diHE-dioxo CH₂OAc 2-nPent-Ph 3-193 dioxo Me 4-F-2-nPent-Ph 3-194 4-HM-dioxo Me 4-F-2-nPent-Ph 3-195 4,5-diHM-dioxo Me 4-F-2-nPent-Ph 3-196 4,5-diHE-dioxo Me 4-F-2-nPent-Ph 3-197 dioxo nPr 4-F-2-nPent-Ph 3-198 4-HM-dioxo nPr 4-F-2-nPent-Ph 3-199 4,5-diHM-dioxo nPr 4-F-2-nPent-Ph 3-200 4,5-diHE-dioxo nPr 4-F-2-nPent-Ph 3-201 dioxo nBu 4-F-2-nPent-Ph 3-202 4-HM-dioxo nBu 4-F-2-nPent-Ph 3-203 4,5-diHM-dioxo nBu 4-F-2-nPent-Ph 3-204 4,5-diHE-dioxo nBu 4-F-2-nPent-Ph 3-205 dioxo iPr 4-F-2-nPent-Ph 3-206 4-HM-dioxo iPr 4-F-2-nPent-Ph 3-207 4,5-diHM-dioxo iPr 4-F-2-nPent-Ph 3-208 4,5-diHE-dioxo iPr 4-F-2-nPent-Ph 3-209 dioxo tBu 4-F-2-nPent-Ph 3-210 4-HM-dioxo tBu 4-F-2-nPent-Ph 3-211 4,5-diHM-dioxo tBu 4-F-2-nPent-Ph 3-212 4,5-diHE-dioxo tBu 4-F-2-nPent-Ph 3-213 dioxo CH₂OAc 4-F-2-nPent-Ph 3-214 4-HM-dioxo CH₂OAc 4-F-2-nPent-Ph 3-215 4,5-diHM-dioxo CH2OAo 4-F-2-nPent-Ph 3-216 4,5-diHE-dioxo CH2OAo 4-F-2-nPent-Ph 3-217 dioxo Me 2-nHex—Ph 3-218 4-HM-dioxo Me 2-nHex—Ph 3-219 4,5-diHM-dioxo Me 2-nHex—Ph 3-220 4,5-diHE-dioxo Me 2-nHex—Ph 3-221 dioxo nPr 2-nHex—Ph 3-222 4-HM-dioxo nPr 2-nHex—Ph 3-223 4,5-diHM-dioxo nPr 2-nHex—Ph 3-224 4,5-diHE-dioxo nPr 2-nHex—Ph 3-225 dioxo nBu 2-nHex—Ph 3-226 4-HM-dioxo nBu 2-nHex—Ph 3-227 4,5-diHM-dioxo nBu 2-nHex—Ph 3-223 4,5-diHE-dioxo nBu 2-nHex—Ph 3-229 dioxo iPr 2-nHex—Ph 3-230 4-HM-dioxo iPr 2-nHex—Ph 3-231 4,5-diHM-dioxo iPr 2-nHex—Ph 3-232 4,5-diHE-dioxo iPr 2-nHex—Ph 3-233 dioxo tBu 2-nHex—Ph 3-234 4-HM-dioxo tBu 2-nHex—Ph 3-235 4,5-diHM-dioxo tBu 2-nHex—Ph 3-236 4,5-diHE-dioxo tBu 2-nHex—Ph 3-237 dioxo CH₂OAc 2-nHex—Ph 3-238 4-HM-dioxo CH₂OAc 2-nHex—Ph 3-239 4,5-diHM-dioxo CH₂OAc 2-nHex—Ph 3-240 4,5-diHE-dioxo CH₂OAc 2-nHex—Ph 3-241 dioxo Me 4-F-nHex—Ph 3-242 4-HM-dioxo Me 4-F-nHex—Ph 3-243 4,5-diHM-dioxo Me 4-F-nHex—Ph 3-244 4,5-diHE-dioxo Me 4-F-nHex—Ph 3-245 dioxo nPr 4-F-nHex—Ph 3-246 4-HM-dioxo nPr 4-F-nHex—Ph 3-247 4,5-diHM-dioxo nPr 4-F-nHex—Ph 3-248 4,5-diHE-dioxo nPr 4-F-nHex—Ph 3-249 dioxo nBu 4-F-nHex—Ph 3-250 4-HM-dioxo nBu 4-F-nHex—Ph 3-251 4,5-diHM-dioxo nBu 4-F-nHex—Ph 3-252 4,5-diHE-dioxo nBu 4-F-nHex—Ph 3-253 dioxo iPr 4-F-nHex—Ph 3-254 4-HM-dioxo iPr 4-F-nHex—Ph 3-255 4,5-diHM-dioxo iPr 4-F-nHex—Ph 3-256 4,5-diHE-dioxo iPr 4-F-nHex—Ph 3-257 dioxo tBu 4-F-nHex—Ph 3-258 4-HM-dioxo tBu 4-F-nHex—Ph 3-259 4,5-diHM-dioxa tBu 4-F-nHex—Ph 3-260 4,5-diHE-dioxo tBu 4-F-nHex—Ph 3-261 dioxo CH₂OAc 4-F-nHex—Ph 3-262 4-HM-dioxo CH₂OAc 4-F-nHex—Ph 3-263 4,5-diHM-dioxo CH₂OAc 4-F-nHex—Ph 3-264 4,5-diHE-dioxo CH2OAC 4-F-nHex—Ph 3-265 dioxo Me 2-nHept-Ph 3-266 4-HM-dioxo Me 2-nHept-Ph 3-267 4,5-diHM-dioxo Me 2-nHept-Ph 3-268 4,5-diHE-dioxo Me 2-nHept-Ph 3-269 dioxo nPr 2-nHept-Ph 3-270 4-HM-dioxo nPr 2-nHept-Ph 3-271 4,5-diHM-dioxo nPr 2-nHept-Ph 3-272 4,5-diHE-dioxo nPr 2-nHept-Ph 3-273 dioxo nBu 2-nHept-Ph 3-274 4-HM-dioxo nBu 2-nHept-Ph 3-275 4,5-diHM-dioxo nBu 2-nHept-Ph 3-276 4,5-diHE-dioxo nBu 2-nHept-Ph 3-277 dioxo iPr 2-nHept-Ph 3-278 4-HM-dioxo iPr 2-nHept-Ph 3-279 4,5-diHM-dioxo iPr 2-nHept-Ph 3-280 4,5-diHE-dioxo iPr 2-nHept-Ph 3-281 dioxo tBu 2-nHept-Ph 3-282 4-HM-dioxo tBu 2-nHept-Ph 3-283 4,5-diHM-dioxo tBu 2-nHept-Ph 3-284 4,5-diHE-dioxo tBu 2-nHept-Ph 3-285 dioxo CH₂OAc 2-nHept-Ph 3-286 4-HM-dioxo CH₂OAc 2-nHept-Ph 3-287 4,5-diHM-dioxo CH₂OAc 2-nHept-Ph 3-288 4,5-diHE-dioxo CH₂OAc 2-nHept-Ph 3-289 dioxo Me 4-F-2-nHept-Ph 3-290 4-HM-dioxo Me 4-F-2-nHept-Ph 3-291 4,5-diHM-dioxo Me 4-F-2-nHept-Ph 3-292 4,5-diHE-dioxo Me 4-F-2-nHept-Ph 3-293 dioxo nPr 4-F-2-nHept-Ph 3-294 4-HM-dioxo nPr 4-F-2-nHept-Ph 3-295 4,5-diHM-dioxo nPr 4-F-2-nHept-Ph 3-296 4,5-diHE-dioxo nPr 4-F-2-nHept-Ph 3-297 dioxo nBu 4-F-2-nHept-Ph 3-298 4-HM-dioxo nBu 4-F-2-nHept-Ph 3-299 4,5-diHM-dioxo nBu 4-F-2-nHept-Ph 3-300 4,5-diHE-dioxo nBu 4-F-2-nHept-Ph 3-301 dioxo iPr 4-F-2-nHept-Ph 3-302 4-HM-dioxo iPr 4-F-2-nHept-Ph 3-303 4,5-diHM-dioxo iPr 4-F-2-nHept-Ph 3-304 4,5-diHE-dioxo iPr 4-F-2-nHept-Ph 3-305 dioxo tBu 4-F-2-nHept-Ph 3-306 4-HM-dioxo tBu 4-F-2-nHept-Ph 3-307 4,5-diHM-dioxo tBu 4-F-2-nHept-Ph 3-308 4,5-diHE-dioxo tBu 4-F-2-nHept-Ph 3-309 dioxo CH₂OAc 4-F-2-nHept-Ph 3-310 4-HM-dioxo CH₂OAc 4-F-2-nHept-Ph 3-311 4,5-diHM-dioxo CH₂OAc 4-F-2-nHept-Ph 3-312 4,5-diHE-dioxo CH₂OAc 4-F-2-nHept-Ph 3-313 dioxo Me 2-nOct-Ph 3-314 4-HM-dioxo Me 2-nOct-Ph 3-315 4,5-diHM-dioxo Me 2-nOct-Ph 3-316 4,5-diHE-dioxo Me 2-nOct-Ph 3-317 dioxo nPr 2-nOct-Ph 3-318 4-HM-dioxo nPr 2-nOct-Ph 3-319 4,5-diHM-dioxo nPr 2-nOct-Ph 3-320 4,5-diHE-dioxo nPr 2-nOct-Ph 3-321 dioxo nBu 2-nOct-Ph 3-322 4-HM-dioxo nBu 2-nOct-Ph 3-323 4,5-diHM-dioxo nBu 2-nOct-Ph 3-324 4,5-diHE-dioxo nBu 2-nOct-Ph 3-325 dioxo iPr 2-nOct-Ph 3-326 4-HM-dioxo iPr 2-nOct-Ph 3-327 4,5-diHM-dioxo iPr 2-nOct-Ph 3-328 4,5-diHE-dioxo iPr 2-nOct-Ph 3-329 dioxo tBu 2-nOct-Ph 3-330 4-HM-dioxo tBu 2-nOct-Ph 3-331 4,5-diHM-dioxo tBu 2-nOct-Ph 3-332 4,5-diHE-dioxo tBu 2-nOct-Ph 3-333 dioxo CH2OAo 2-nOct-Ph 3-334 4-HM-dioxo CH₂OAc 2-nOct-Ph 3-335 4,5-diHM-dioxo CH₂OAc 2-nOct-Ph 3-336 4,5-diHE-dioxo CH₂OAc 2-nOct-Ph 3-337 dioxo Me 4-F-2-nOct-Ph 3-338 4-HM-dioxo Me 4-F-2-nOct-Ph 3-339 4,5-diHM-dioxo Me 4-F-2-nOct-Ph 3-340 4,5-diHE-dioxo Me 4-F-2-nOct-Ph 3-341 dioxo nPr 4-F-2-nOct-Ph 3-342 4-HM-dioxo nPr 4-F-2-nOct-Ph 3-343 4,5-diHM-dioxo nPr 4-F-2-nOct-Ph 3-344 4,5-diHE-dioxo nPr 4-F-2-nOct-Ph 3-345 dioxo nBu 4-F-2-nOct-Ph 3-346 4-HM-dioxo nBu 4-F-2-nOct-Ph 3-347 4,5-diHM-dioxo nBu 4-F-2-nOct-Ph 3-348 4,5-diHE-dioxo nBu 4-F-2-nOct-Ph 3-349 dioxo iPr 4-F-2-nOct-Ph 3-350 4-HM-dioxo iPr 4-F-2-nOct-Ph 3-351 4,5-diHM-dioxo iPr 4-F-2-nOct-Ph 3-352 4,5-diHE-dioxo iPr 4-F-2-nOct-Ph 3-353 dioxo tBu 4-F-2-nOct-Ph 3-354 4-HM-dioxo tBu 4-F-2-nOct-Ph 3-355 4,5-diHM-dioxo tBu 4-F-2-nOct-Ph 3-356 4,5-diHE-dioxo tBu 4-F-2-nOct-Ph 3-357 dioxo CH₂OAc 4-F-2-nOct-Ph 3-358 4-HM-dioxo CH₂OAc 4-F-2-nOct-Ph 3-359 4,5-diHM-dioxo CH₂OAc 4-F-2-nOct-Ph 3-360 4,5-diHE-dioxo CH₂OAc 4-F-2-nOct-Ph 3-361 dioxo Me Ph 3-362 4-HM-dioxo Me Ph 3-363 4,5-diHM-dioxo Me Ph 3-364 4,5-diHE-dioxo Me Ph 3-365 dioxo nPr Ph 3-366 4-HM-dioxo nPr Ph 3-367 4,5-diHM-dioxo nPr Ph 3-368 4,5-diHE-dioxo nPr Ph 3-369 dioxo nBu Ph 3-370 4-HM-dioxo nBu Ph 3-371 4,5-diHM-dioxo nBu Ph 3-372 4,5-diHE-dioxo nBu Ph 3-373 dioxo iPr Ph 3-374 4-HM-dioxo iPr Ph 3-375 4,5-diHM-dioxo iPr Ph 3-376 4,5-diHE-dioxo iPr Ph 3-377 dioxo tBu Ph 3-378 4-HM-dioxo tBu Ph 3-379 4,5-diHM-dioxo tBu Ph 3-380 4,5-diHE-dioxo tBu Ph 3-381 dioxo CH₂OAc Ph 3-382 4-HM-dioxo CH₂OAc Ph 3-383 4,5-diHM-dioxo CH₂OAc Ph 3-384 4,5-diHE-dioxo CH₂OAc Ph 3-385 dioxo Me 4-F—Ph 3-386 4-HM-dioxo Me 4-F—Ph 3-387 4,5-diHM-dioxo Me 4-F—Ph 3-388 4,5-diHE-dioxo Me 4-F—Ph 3-389 dioxo nPr 4-F—Ph 3-390 4-HM-dioxo nPr 4-F—Ph 3-391 4.5-diHM-dioxo nPr 4-F—Ph 3-392 4,5-diHE-dioxo nPr 4-F—Ph 3-393 dioxo nBu 4-F—Ph 3-394 4-HM-dioxo nBu 4-F—Ph 3-395 4,5-diHM-dioxo nBu 4-F—Ph 3-396 4,5-diHE-dioxo nBu 4-F—Ph 3-397 dioxo iPr 4-F—Ph 3-398 4-HM-dioxo iPr 4-F—Ph 3-399 4,5-diHM-dioxo iPr 4-F—Ph 3-400 4,5-diHE-dioxo iPr 4-F—Ph 3-401 dioxo tBu 4-F—Ph 3-402 4-HM-dioxo tBu 4-F—Ph 3-403 4,5-diHM-dioxo tBu 4-F—Ph 3-404 4,5-diHE-dioxo tBu 4-F—Ph 3-405 dioxo CH₂OAc 4-F—Ph 3-406 4-HM-dioxo CH₂OAc 4-F—Ph 3-407 4,5-diHM-dioxo CH₂OAc 4-F—Ph 3-408 4,5-diHE-dioxo CH₂OAc 4-F—Ph 3-409 dioxo Me 2-Cl-4-Me—Ph 3-410 4-HM-dioxo Me 2-Cl-4-Me—Ph 3-411 4,5-diHM-dioxo Me 2-Cl-4-Me—Ph 3-412 4,5-diHE-dioxo Me 2-Cl-4-Me—Ph 3-413 dioxo nPr 2-Cl-4-Me—Ph 3-414 4-HM-dioxo nPr 2-Cl-4-Me—Ph 3-415 4,5-diHM-dioxo nPr 2-Cl-4-Me—Ph 3-416 4,5-diHE-dioxo nPr 2-Cl-4-Me—Ph 3-417 dioxo nBu 2-Cl-4-Me—Ph 3-418 4-HM-dioxo nBu 2-Cl-4-Me—Ph 3-419 4,5-diHM-dioxo nBu 2-Cl-4-Me—Ph 3-420 4,5-diHE-dioxo nBu 2-Cl-4-Me—Ph 3-421 dioxo iPr 2-Cl-4-Me—Ph 3-422 4-HM-dioxo iPr 2-Cl-4-Me—Ph 3-423 4,5-diHM-dioxo iPr 2-Cl-4-Me—Ph 3-424 4,5-diHE-dioxo iPr 2-Cl-4-Me—Ph 3-425 dioxo tBu 2-Cl-4-Me—Ph 3-426 4-HM-dioxo tBu 2-Cl-4-Me—Ph 3-427 4,5-diHM-dioxo tBu 2-Cl-4-Me—Ph 3-428 4,5-diHE-dioxo tBu 2-Cl-4-Me—Ph 3-429 dioxo CH₂OAc 2-Cl-4-Me—Ph 3-430 4-HM-dioxo CH₂OAc 2-Cl-4-Me—Ph 3-431 4,5-diHM-dioxo CH₂OAc 2-Cl-4-Me—Ph 3-432 4,5-diHE-dioxo CH₂OAc 2-Cl-4-Me—Ph 3-433 dioxo Me 2-nBu—Ph 3-434 4-HM-dioxo Me 2-nBu—Ph 3-435 4,5-diHM-dioxo Me 2-nBu—Ph 3-436 4,5-diHE-dioxo Me 2-nBu—Ph 3-437 dioxo nPr 2-nBu—Ph 3-438 4-HM-dioxo nPr 2-nBu—Ph 3-439 4,5-diHM-dioxo nPr 2-nBu—Ph 3-440 4,5-diHE-dioxo nPr 2-nBu—Ph 3-441 dioxo nBu 2-nBu—Ph 3-442 4-HM-dioxo nBu 2-nBu—Ph 3-443 4,5-diHM-dioxo nBu 2-nBu—Ph 3-444 4,5-diHE-dioxo nBu 2-nBu—Ph 3-445 dioxo iPr 2-nBu—Ph 3-446 4-HM-dioxo iPr 2-nBu—Ph 3-447 4,5-diHM-dioxo iPr 2-nBu—Ph 3-448 4,5-diHE-dioxo iPr 2-nBu—Ph 3-449 dioxo tBu 2-nBu—Ph 3-450 4-HM-dioxo tBu 2-nBu—Ph 3-451 4,5-diHM-dioxo tBu 2-nBu—Ph 3-452 4,5-diHE-dioxo tBu 2-nBu—Ph 3-453 dioxo CH₂OAc 2-nBu—Ph 3-454 4-HM-dioxo CH₂OAc 2-nBu—Ph 3-455 4,5-diHM-dioxo CH₂OAc 2-nBu—Ph 3-456 4,5-diHE-dioxo CH₂OAc 2-nBu—Ph 3-457 dioxo Me 2-nPr—Ph 3-458 4-HM-dioxo Me 2-nPr—Ph 3-459 4,5-diHM-dioxo Me 2-nPr—Ph 3-460 4,5-diHE-dioxo Me 2-nPr—Ph 3-461 dioxo nPr 2-nPr—Ph 3-462 4-HM-dioxo nPr 2-nPr—Ph 3-463 4,5-diHM-dioxo nPr 2-nPr—Ph 3-464 4,5-diHE-dioxo nPr 2-nPr—Ph 3-465 dioxo nBu 2-nPr—Ph 3-466 4-HM-dioxo nBu 2-nPr—Ph 3-467 4.5-diHM-dioxo nBu 2-nPr—Ph 3-468 4,5-diHE-dioxo nBu 2-nPr—Ph 3-469 dioxo iPr 2-nPr—Ph 3-470 4-HM-dioxo iPr 2-nPr—Ph 3-471 4,5-diHM-dioxo iPr 2-nPr—Ph 3-472 4,5-diHE-dioxo iPr 2-nPr—Ph 3-473 dioxo tBu 2-nPr—Ph 3-474 4-HM-dioxo tBu 2-nPr—Ph 3-475 4,5-diHM-dioxo tBu 2-nPr—Ph 3-476 4,5-diHE-dioxo tBu 2-nPr—Ph 3-477 dioxo CH₂OAc 2-nPr—Ph 3-478 4-HM-dioxo CH₂OAc 2-nPr—Ph 3-479 4,5-diHM-dioxo CH₂OAc 2-nPr—Ph 3-480 4,5-diHE-dioxo CH₂OAc 2-nPr—Ph 3-481 dioxo Me 4-F-2-nPr—Ph 3-482 4-HM-dioxo Me 4-F-2-nPr—Ph 3-483 4,5-diHM-dioxo Me 4-F-2-nPr—Ph 3-484 4,5-diHE-dioxo Me 4-F-2-nPr—Ph 3-485 dioxo nPr 4-F-2-nPr—Ph 3-486 4-HM-dioxo nPr 4-F-2-nPr—Ph 3-487 4,5-diHM-dioxo nPr 4-F-2-nPr—Ph 3-488 4,5-diHE-dioxo nPr 4-F-2-nPr—Ph 3-489 dioxo nBu 4-F-2-nPr—Ph 3-490 4-HM-dioxo nBu 4-F-2-nPr—Ph 3-491 4,5-diHM-dioxo nBu 4-F-2-nPr—Ph 3-492 4,5-diHE-dioxo nBu 4-F-2-nPr—Ph 3-493 dioxo iPr 4-F-2-nPr—Ph 3-494 4-HM-dioxo iPr 4-F-2-nPr—Ph 3-495 4,5-diHM-dioxo iPr 4-F-2-nPr—Ph 3-496 4,5-diHE-dioxo iPr 4-F-2-nPr—Ph 3-497 dioxo tBu 4-F-2-nPr—Ph 3-498 4-HM-dioxo tBu 4-F-2-nPr—Ph 3-499 4,5-diHM-dioxo tBu 4-F-2-nPr—Ph 3-500 4,5-diHE-dioxo tBu 4-F-2-nPr—Ph 3-501 dioxo CH₂OAc 4-F-2-nPr—Ph 3-502 4-HM-dioxo CH₂OAc 4-F-2-nPr—Ph 3-503 4,5-diHM-dioxo CH₂OAc 4-F-2-nPr—Ph 3-504 4,5-diHE-dioxo CH₂OAc 4-F-2-nPr—Ph

In the compounds having the general formula (I) of the present invention, as preferred compounds exemplified compound Nos.: 1-12, 1-13, 1-19, 1-20, 1-26, 1-28, 1-30, 1-32, 1-34, 1-36, 1-38, 1-40, 1-42, 1-44, 1-46, 1-48, 1-50, 1-54, 1-58, 1-60, 1-62, 1-66, 1-68, 1-70, 1-72, 1-74, 1-78, 1-80, 1-82, 1-86, 1-100, 1-101, 1-107, 1-108, 1-114, 1-116, 1-118, 1-120, 1-122, 1-124, 1-126, 1-128, 1-130, 1-132, 1-134, 1-136, 1-138, 1-142, 1-146, 1-148, 1-150, 1-154, 1-156, 1-158, 1-160, 1-162, 1-166, 1-168, 1-170, 1-174, 1-188, 1-189, 1-195, 1-196, 1-202, 1-204, 1-206, 1-208, 1-210, 1-212, 1-214, 1-216, 1-218, 1-220, 1-222, 1-224, 1-226, 1-230, 1-234, 1-236, 1-238, 1-242, 1-244, 1-246, 1-248, 1-250, 1-254, 1-256, 1-258, 1-262, 1-276, 1-277, 1-283, 1-284, 1-290, 1-292, 1-294, 1-296, 1-298, 1-300, 1-302, 1-304, 1-306, 1-308, 1-310, 1-312, 1-314, 1-318, 1-322, 1-324, 1-326, 1-330, 1-332, 1-334, 1-336, 1-338, 1-342, 1-344, 1-346, 1-350, 1-353, 1-355, 1-360 to 1-369, 1-371, 1-372, 1-378, 1-380, 1-382, 1-384, 1-386, 1-388, 1-390, 1-392, 1-394, 1-396, 1-398, 1-400, 1-402, 1-406, 1-410, 1-412, 1-414, 1-418, 1-420, 1-422, 1-424, 1-426, 1-430, 1-432, 1-434, 1-438, 1-452, 1-453, 1-459, 1-460, 1-466, 1-468, 1-470, 1-472, 1-474, 1-476, 1-478, 1-480, 1-482, 1-484, 1-486, 1-488, 1-490, 1-494, 1-498, 1-500, 1-502, 1-506, 1-508, 1-510, 1-512, 1-514, 1-518, 1-520, 1-522, 1-526, 1-540, 1-541, 1-547, 1-548, 1-554, 1-556, 1-558, 1-560, 1-562, 1-564, 1-566, 1-568, 1-570, 1-572, 1-574, 1-576, 1-578, 1-582, 1-586, 1-588, 1-590, 1-594, 1-596, 1-598, 1-600, 1-602, 1-604, 1-606, 1-608, 1-610, 1-614, 1-628, 1-629, 1-635, 1-636, 1-642, 1-644, 1-646, 1-648, 1-650, 1-652, 1-654, 1-656, 1-658, 1-660, 1-662, 1-664, 1-666, 1-670, 1-674, 1-676, 1-678, 1-682, 1-684, 1-686, 1-688, 1-690, 1-694, 1-696, 1-698, 1-702, 1-712 to 1-720, 1-723, 1-724, 1-730, 1-732, 1-734, 1-736, 1-738, 1-740, 1-742, 1-744, 1-746, 1-748, 1-750, 1-752, 1-754, 1-758, 1-762, 1-764, 1-766, 1-770, 1-772, 1-774, 1-776, 1-778, 1-782, 1-784, 1-786, 1-790, 1-804, 1-805, 1-811, 1-812, 1-818, 1-820, 1-822, 1-824, 1-826, 1-828, 1-830, 1-832, 1-834, 1-836, 1-838, 1-840, 1-842, 1-846, 1-850, 1-852, 1-854, 1-858, 1-860, 1-862, 1-864, 1-866, 1-870, 1-872, 1-874, 1-878, 1-888 to 1-896, 1-899, 1-900, 1-906, 1-908, 1-910, 1-912, 1-914, 1-916, 1-918, 1-920, 1-922, 1-924, 1-926, 1-928, 1-930, 1-934, 1-938, 1-940, 1-942, 1-946, 1-948, 1-950, 1-952, 1-954, 1-958, 1-960, 1-962, 1-966, 1-980, 1-981, 1-987, 1-988, 1-994, 1-996, 1-998, 1-1000, 1-1002, 1-1004, 1-1006, 1-1008, 1-1010, 1-1012, 1-1014, 1-1016, 1-1018, 1-1022, 1-1026, 1-1028, 1-1030, 1-1034, 1-1036, 1-1038, 1-1040, 1-1042, 1-1046, 1-1048, 1-1050, 1-1054, 1-1057, 1-1062, 1-1063, 1-1066, 1-1067 to 1-1070, 1-1074, 1-1079, 1-1080, 1-1083, 1-1085 to 1-1087, 1-1091, 1-1096, 1-1097, 1-1100, 1-1102 to 1-1104, 1-1108, 1-1113, 1-1114, 1-1117, 1-1119 to 1-1121, 1-1125, 1-1130, 1-1131, 1-1134, 1-1136 to 1-1138, 1-1142, 1-1147, 1-1148, 1-1151, 1-1153 to 1-1155, 1-1159, 1-1164, 1-1165, 1-1168, 1-1170 to 1-1172, 1-1176, 1-1181, 1-1182, 1-1185, 1-1187 to 1-1189, 1-1193, 1-1198, 1-1199, 1-1202, 1-1204 to 1-1206, 1-1210, 1-1215, 1-1216, 1-1219, 1-1221 to 1-1223, 1-1227, 1-1232, 1-1233, 1-1236, 1-1238 to 1-1240, 1-1244, 1-1249, 1-1250, 1-1253, 1-1255 to 1-1257, 1-1261, 1-1266, 1-1267, 1-1270, 1-1272 to 1-1274, 1-1278, 1-1283, 1-1284, 1-1287, 1-1289 to 1-1291, 1-1295, 1-1300, 1-1301, 1-1304, 1-1306 to 1-1308, 1-1312, 1-1317, 1-1318, 1-1321, 1-1323 to 1-1325, 1-1329, 1-1334, 1-1335, 1-1337, 1-1340 to 1-1342, 1-1346, 1-1351, 1-1352, 1-1355, 1-1357 to 1-1359, 1-1374, 1-1375, 1-1381, 1-1382, 1-1388, 1-1390, 1-1392, 1-1394, 1-1396, 1-1398, 1-1400, 1-1402, 1-1404, 1-1406, 1-1408, 1-1410, 1-1412, 1-1416, 1-1420, 1-1422, 1-1428, 1-1430, 1-1432, 1-1434, 1-1436, 1-1440, 1-1442, 1-1444, 1-1448, 1-1462, 1-1463, 1-1469, 1-1470, 1-1476, 1-1478, 1-1480, 1-1482, 1-1484, 1-1486, 1-1488, 1-1490, 1-1492, 1-1494, 1-1496, 1-1498, 1-1500, 1-1504, 1-1508, 1-1510, 1-1516, 1-1518, 1-1520, 1-1522, 1-1524, 1-1528, 1-1530, 1-1532, 1-1536, 1-1550, 1-1551, 1-1557, 1-1558, 1-1564, 1-1566, 1-1568, 1-1570, 1-1572, 1-1574, 1-1576, 1-1578, 1-1580, 1-1582, 1-1584, 1-1586, 1-1588, 1-1592, 1-1596, 1-1598, 1-1604, 1-1606, 1-1608, 1-1610, 1-1612, 1-1616, 1-1618, 1-1620, 1-1624, 1-1638, 1-1639, 1-1645, 1-1646, 1-1652, 1-1654, 1-1656, 1-1658, 1-1660, 1-1662, 1-1664, 1-1666, 1-1668, 1-1670, 1-1672, 1-1674, 1-1676, 1-1680, 1-1684, 1-1686, 1-1692, 1-1694, 1-1696, 1-1698, 1-1700, 1-1704, 1-1706, 1-1708, 1-1712, 1-1726, 1-1727, 1-1733, 1-1734, 1-1740, 1-1742, 1-1744, 1-1746, 1-1748, 1-1750, 1-1752, 1-1754, 1-1756, 1-1758, 1-1760, 1-1762, 1-1764, 1-1768, 1-1772, 1-1774, 1-1780, 1-1782, 1-1784, 1-1786, 1-1788, 1-1792, 1-1794, 1-1796, 1-1800, 1-1814, 1-1815, 1-1821, 1-1822, 1-1828, 1-1830, 1-1832, 1-1834, 1-1836, 1-1838, 1-1840, 1-1842, 1-1844, 1-1846, 1-1848, 1-1850, 1-1852, 1-1856, 1-1860, 1-1862, 1-1868, 1-1870, 1-1872, 1-1874, 1-1876, 1-1880, 1-1882, 1-1884, 1-1888, 1-1902, 1-1903, 1-1909, 1-1910, 1-1916, 1-1918, 1-1920, 1-1922, 1-1924, 1-1926, 1-1928, 1-1930, 1-1932, 1-1934, 1-1936, 1-1938, 1-1940, 1-1944, 1-1948, 1-1950, 1-1956, 1-1958, 1-1960, 1-1962, 1-1964, 1-1968, 1-1970, 1-1972, 1-1976, 1-1989, 1-1990, 1-1996, 1-1997, 1-2003, 1-2005, 1-2007, 1-2009, 1-2011, 1-2013, 1-2015, 1-2017, 1-2019, 1-2021, 1-2023, 1-2025, 1-2027, 1-2031, 1-2035, 1-2037, 1-2043, 1-2045, 1-2047, 1-2049, 1-2051, 1-2055, 1-2057, 1-2059, 1-2063, 1-2077, 1-2078, 1-2084, 1-2085, 1-2091, 1-2093, 1-2095, 1-2097, 1-2099, 1-2101, 1-2103, 1-2105, 1-2107, 1-2109, 1-2111, 1-2113, 1-2115, 1-2119, 1-2123, 1-2125, 1-2131, 1-2133, 1-2135, 1-2137, 1-2139, 1-2143, 1-2145, 1-2147, 1-2151, 1-2154, 1-2157, 1-2160, 1-2163, 1-2166, 1-2169, 1-2172, 1-2175, 1-2178, 1-2181, 1-2184, 1-2187, 1-2190, 1-2193, 1-2196, 1-2199, 1-2202, 1-2205, 1-2208, 1-2211, 1-2214, 1-2217 to 1-2221, 1-2224 to 1-2228, 1-2231 to 1-2235, 1-2238 to 1-2242, 1-2245 to 1-2249, 1-2252 to 1-2256, 1-2259 to 1-2263, 1-2266 to 1-2270, 1-2273 to 1-2277, 1-2280 to 1-2284, 1-2287 to 1-2291, 1-2294 to 1-2298, 1-2301 to 1-2305, 1-2308 to 1-2312, 1-2315 to 1-2319, 1-2322 to 1-2326, 1-2329 to 1-2333, 1-2336 to 1-2340, 1-2343 to 1-2347, 1-2350 to 1-2354, 1-2357 to 1-2361, 1-2364 to 1-2368, 1-2371 to 1-2375, 1-2378 to 1-2382, 1-2385 to 1-2389, 1-2392 to 1-2396, 1-2399 to 1-2403, 1-2406 to 1-2410, 1-2413 to 1-2417, 1-2420 to 1-2424, 1-2427 to 1-2431, 1-2434 to 1-2438, 1-2441 to 1-2445, 1-2448 to 1-2452, 1-2455 to 1-2459, 1-2462 to 1-2466, 1-2469 to 1-2473, 1-2476 to 1-2480, 1-2483 to 1-2487, 1-2490 to 1-2494, 1-2497 to 1-2501, 1-2504 to 1-2508, 1-2511 to 1-2515, 1-2518 to 1-2522, 1-2525 to 1-2529, 1-2532 to 1-2536, 1-2539 to 1-2543, 1-2546 to 1-2550, 1-2553 to 1-2557, 1-2560 to 1-2564, 1-2567 to 1-2571, 1-2574 to 1-2578, 1-2581 to 1-2585, 1-2588 to 1-2592, 1-2595 to 1-2599, 1-2602 to 1-2606, 1-2609 to 1-2613, 1-2616 to 1-2620, 1-2623 to 1-2627, 2-3, 2-4, 2-7, 2-8, 2-11, 2-12, 2-15, 2-16, 2-19, 2-20, 2-23, 2-24, 2-27, 2-28, 2-31, 2-32, 2-35, 2-36, 2-39, 2-40, 2-43, 2-44, 2-47, 2-48, 2-51, 2-52, 2-59, 2-60, 2-83, 2-84, 3-3, 3-4, 3-7, 3-8, 3-11, 3-12, 3-15, 3-16, 3-27, 3-28, 3-31, 3-32, 3-35, 3-36, 3-39, 3-40, 3-51, 3-52, 3-55, 3-56, 3-59, 3-60, 3-63, 3-64, 3-75, 3-76, 3-79, 3-80, 3-83, 3-84, 3-87, 3-88, 3-99, 3-100, 3-103, 3-104, 3-107, 3-108, 3-111, 3-112, 3-123, 3-124, 3-127, 3-128, 3-131, 3-132, 3-135, 3-136, 3-147, 3-148, 3-151, 3-152, 3-155, 3-156, 3-159, 3-160, 3-171, 3-172, 3-175, 3-176, 3-179, 3-180, 3-183, 3-184, 3-195, 3-196, 3-199, 3-200, 3-203, 3-204, 3-207, 3-208, 3-219, 3-220, 3-223, 3-224, 3-227, 3-228, 3-231, 3-232, 3-243, 3-244, 3-247, 3-248, 3-251, 3-252, 3-255, 3-256, 3-267, 3-268, 3-271, 3-272, 3-275, 3-276, 3-279, 3-280, 3-291, 3-292, 3-295, 3-296, 3-299, 3-300, 3-303, 3-304, 3-339, 3-340, 3-343, 3-344, 3-347, 3-348, 3-351, 3-352, 3-483, 3-484, 3-487, 3-488, 3-491, 3-492, 3-495, and 3-496 can be mentioned,

more preferably, exemplified compound Nos.: 1-12, 1-26, 1-30, 1-34, 1-38, 1-42, 1-46, 1-58, 1-66, 1-70, 1-78, 1-100, 1-114, 1-118, 1-122, 1-126, 1-130, 1-134, 1-146, 1-154, 1-158, 1-166, 1-188, 1-202, 1-206, 1-210, 1-214, 1-218, 1-222, 1-234, 1-242, 1-246, 1-254, 1-276, 1-290, 1-294, 1-298, 1-302, 1-306, 1-310, 1-322, 1-330, 1-334, 1-342, 1-364, 1-378, 1-382, 1-386, 1-390, 1-394, 1-398, 1-410, 1-418, 1-422, 1-430, 1-452, 1-466, 1-470, 1-474, 1-478, 1-482, 1-486, 1-498, 1-506, 1-510, 1-518, 1-540, 1-554, 1-558, 1-562, 1-566, 1-570, 1-574, 1-586, 1-594, 1-598, 1-604, 1-606, 1-628, 1-642, 1-646, 1-650, 1-654, 1-658, 1-662, 1-674, 1-682, 1-686, 1-694, 1-716, 1-730, 1-734, 1-738, 1-742, 1-746, 1-750, 1-762, 1-770, 1-774, 1-782, 1-804, 1-818, 1-822, 1-826, 1-830, 1-834, 1-838, 1-850, 1-858, 1-862, 1-870, 1-892, 1-906, 1-910, 1-914, 1-918, 1-922, 1-926, 1-938, 1-946, 1-950, 1-958, 1-980, 1-994, 1-998, 1-1002, 1-1006, 1-1010, 1-1014, 1-1026, 1-1034, 1-1038, 1-1046, 1-1227, 1-1232, 1-1239, 1-1240, 1-1244, 1-1249, 1-1256, 1-1257, 1-1261, 1-1266, 1-1273, 1-1274, 1-1278, 1-1283, 1-1290, 1-1291, 1-1295, 1-1300, 1-1307, 1-1308, 1-1374, 1-1388, 1-1392, 1-1396, 1-1400, 1-1404, 1-1408, 1-1420, 1-1428, 1-1432, 1-1440, 1-1462, 1-1476, 1-1480, 1-1484, 1-1488, 1-1492, 1-1496, 1-1508, 1-1516, 1-1520, 1-1528, 1-1550, 1-1564, 1-1568, 1-1572, 1-1576, 1-1580, 1-1584, 1-1596, 1-1604, 1-1608, 1-1616, 1-1638, 1-1652, 1-1656, 1-1660, 1-1664, 1-1668, 1-1672, 1-1684, 1-1692, 1-1696, 1-1704, 1-1726, 1-1740, 1-1744, 1-1748, 1-1752, 1-1756, 1-1760, 1-1772, 1-1780, 1-1784, 1-1792, 1-1814, 1-1828, 1-1832, 1-1836, 1-1840, 1-1844, 1-1848, 1-1860, 1-1868, 1-1872, 1-1880, 1-1902, 1-1916, 1-1920, 1-1924, 1-1928, 1-1932, 1-1936, 1-1948, 1-1956, 1-1960, 1-1968, 1-1989, 1-2003, 1-2007, 1-2011, 1-2015, 1-2019, 1-2023, 1-2035, 1-2043, 1-2047, 1-2055, 1-2077, 1-2091, 1-2095, 1-2099, 1-2103, 1-2107, 1-2111, 1-2123, 1-2131, 1-2135, 1-2143, 1-2219, 1-2220, 1-2226, 1-2227, 1-2233, 1-2234, 1-2240, 1-2241, 1-2247, 1-2248, 1-2254, 1-2255, 1-2261, 1-2262, 1-2268, 1-2269, 1-2275, 1-2276, 1-2282, 1-2283, 1-2289, 1-2290, 1-2296, 1-2297, 1-2303, 1-2304, 1-2310, 1-2311, 1-2317, 1-2318, 1-2324, 1-2325, 1-2331, 1-2332, 1-2338, 1-2339, 1-2345, 1-2346, 1-2352, 1-2353, 1-2359, 1-2360, 1-2366, 1-2367, 1-2373, 1-2374, 1-2380, 1-2381, 1-2387, 1-2388, 1-2394, 1-2395, 1-2401, 1-2402, 1-2408, 1-2409, 1-2415, 1-2416, 1-2422, 1-2423, 1-2429, 1-2430, 1-2436, 1-2437, 1-2443, 1-2444, 1-2450, 1-2451, 1-2457, 1-2458, 1-2464, 1-2465, 1-2471, 1-2472, 1-2478, 1-2479, 1-2485, 1-2486, 1-2492, 1-2493, 1-2499, 1-2500, 1-2506, 1-2507, 1-2513, 1-2514, 1-2520, 1-2521, 1-2527, 1-2528, 1-2534, 1-2535, 1-2541, 1-2542, 1-2548, 1-2549, 1-2555, 1-2556, 1-2562, 1-2563, 1-2569, 1-2570, 1-2576, 1-2577, 1-2583, 1-2584, 1-2590, 1-2591, 1-2597, 1-2598, 1-2604, 1-2605, 1-2611, 1-2612, 1-2618, 1-2619, 1-2625, 1-2626, 2-3, 2-7, 2-11, 2-15, 2-19, 2-23, 2-27, 2-31, 2-35, 2-39, 2-43, 2-47, 2-51, 2-59, 2-83, 3-7, 3-31, 3-55, 3-79, 3-103, 3-127, 3-151, 3-175, 3-199, 3-223, 3-247, 3-271, 3-295, 3-343 and 3-487can be mentioned, even more preferably,

-   exemplified compound No. 1-206: ethyl     8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-210: ethyl     8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-294: ethyl     8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-298: ethyl     8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-378: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-382: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-386: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-390: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-394: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3-trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-398: ethyl     8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-410: ethyl     2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-418: ethyl     9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, -   exemplified compound No. 1-422: ethyl     3-acetylamino-9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, -   exemplified compound No. 1-430: ethyl     9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5-dioxaspiro[5.5]     undec-7-ene-8-carboxylate, -   exemplified compound No. 1-646: ethyl     8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-650: ethyl     8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-734: ethyl     8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-738: ethyl 8-[N-(2-hexyl     phenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-822: ethyl     8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-826: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-910: ethyl     8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-914: ethyl     8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-998: ethyl     8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1002: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1392: ethyl     8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1396: ethyl     8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1480: ethyl     8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1484: ethyl     8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1568: ethyl     8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1572: ethyl     8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1656: ethyl     2,3-bis(hydroxymethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1660: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1744: ethyl     8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1748: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1920: ethyl     8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-1924: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-2095: ethyl     8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, -   exemplified compound No. 1-2099: ethyl     2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate     and -   exemplified compound No. 2-15: ethyl     8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate     can be mentioned.

The compound having the general formula (I) according to the present invention can easily be prepared in accordance with Method A to Method C shown hereafter.

Method A is a method to prepare a compound having the general formula (I), by introducing a cyclic ketal in the initial stage of the preparation.

Method B is a method to prepare a compound having the general formula (I), by introducing a cyclic ketal in the final stage of the preparation.

Method C is a method to prepare a compound having the general formula (I), by introducing R⁵ in the final stage of the preparation.

In the aforementioned Method A to Method C, ring A, ring B, X, Y, R¹, R², R³, R⁵, m and n have the same meanings as defined above, L represents a leaving group and Z represents a protective group.

In the reactions of Method A to Method C, in the case where the compound as the reactive substrate has a group such as an amino group, hydroxy group and/or carboxyl group, which inhibits the intended reaction, these groups may be protected with a protective group as necessary. The protective group of a group which inhibits the intended reaction is not limited so long as it is a protective group which is ordinarily used to conduct the reaction, and may be, for example, a protective w group described in “Protective Groups in Organic Synthesis, 3^(rd) edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc.”

A protective group of an amino group can be used without particular limitation so long as it is a group generally used as a protective group of an amino group, and preferably, formyl, the aforementioned C₁-C₆ alkylcarbonyl group; the aforementioned arylcarbonyl group; the aforementioned C₁-C₆ alkoxycarbonyl group; the aforementioned C₁-C₆ alkanoyl group which is substituted with halogen; aralkyl groups such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl or 9-anthrylmethyl; the aforementioned aralkyloxycarbonyl group and the like can be mentioned.

A protective group of a hydroxy group can be used without particular limitation so long as it is a group generally used as a protective group of a hydroxy group, and preferably, formyl, C₁-C₆ alkylcarbonyl groups such as acetyl, arylcarbonyls such as benzoyl group; and alkoxylated alkoxymethyls such as 2-methoxyethoxymethyl can be mentioned.

A protective group of a carboxyl group can be used without particular limitation so long as it is a group generally used as a protective group of a carboxyl group, and preferably, the aforementioned C₁-C₆ alkyl group; and aralkyl groups such as benzyl, phenethyl and phenylpropyl can be mentioned.

Further, these protective groups of groups which inhibit the intended reaction may be cleaved as necessary. The cleavage reaction of these protective groups, which is the desired reaction, may be conducted in accordance with conventional procedures which are used in the field of synthetic organic chemistry (for example, the procedure described in the aforementioned Protective Groups in Organic Synthesis, 3^(rd) edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc).

<Method A>

Step 1 of Method A is a step to react a ketone compound (1) with a compound (2) or a compound (3), which is compound (2) having its terminal substituted with a trimethylsilyl group (described as TMS in the aforementioned scheme), in an inert solvent in the presence of acid, to prepare a cyclic ketal compound (4).

This step can adopt a cyclic ketalation reaction (protection) of a ketone, which is widely used in general organic synthesis, and can be conducted in accordance with the procedure described in T. W. Greene, P. C. Wuts, Protective Groups in organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the like, or in accordance with similar procedures.

Here, the cyclic ketal compound (4) can also be prepared by the following procedure (Step 1′ of Method A).

Step 1′ of Method A is a step to react a dimethylketal compound (5) with compound (2) or compound (3), in an inert solvent in the presence of acid, to prepare a cyclic ketal compound (4). This reaction can be conducted in accordance with the same procedure as or based on the procedure of Step 1.

Step 2 of Method A is a step to allow the cyclic ketal compound (4) obtained by Step 1 or Step 1′ to undergo a Dieckmann reaction, to prepare a ketoester compound (7).

This step can adopt a Dieckmann reaction which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.) Vol. 29, pp. 3238-3248 (1981) and the like, or based on that procedure.

Here, the ketoester compound (7) can also be prepared by the following procedure (Step 2′ of Method A).

Step 2′ of Method A is a step to react a ketone compound (6) with a dialkyl carbonate, in an inert solvent in the presence of base, to prepare a ketoester compound (7).

This step can adopt an ester group introducing reaction which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in Canadian Journal of Chemistry (Can. J. Chem.) Vol. 70, pp. 1406-1426 (1992) and the like, or based on that procedure.

Step 3 of Method A is a step to enolate the ketoester compound (7) obtained in Step 2 or Step 2′, in an inert solvent in the presence of base, to prepare a compound (8) having a leaving group L.

This step can be conducted in accordance with the procedure described in Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 120, pp. 3664-3670 (1998) and the like, or based on that procedure.

“Leaving group” in the definition of L generally represents a group which leaves as a nucleophilic residue, and for example, halogen atoms such as a fluorine atom, chlorine atom, bromine atom and iodine atom; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy can be mentioned. Preferably, it is a halogeno lower alkanesulfonyloxy group, particularly preferably a trifluoromethanesulfonyloxy group.

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone and hexamethylphosphorotriamide; or a solvent mixture of these can be mentioned. Preferably, it is a halogenated hydrocarbon, more preferably dichloromethane.

The base used includes inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal fluorides such as sodium fluoride and potassium fluoride; organic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal hydrides or organic bases, and more preferably sodium hydride or diisopropylethylamine.

Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from −100° C. to 100° C., preferably from −78° C. to 50° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 48 hours, preferably from 5 minutes to 12 hours.

Step 4 of Method A is a step to react the compound (8) having a leaving group L obtained in Step 3 with a thiol compound (9) in an inert solvent in the presence of a base, to prepare compound (10).

“Protective group” of the sulfanyl group in the definition of Z is not particularly limited so long as it is a protective group of a sulfanyl group which is widely used generally in organic synthesis, and alkanoyl groups such as formyl, acetyl, propionyl and butyryl, and arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, pyridoyl, thienoyl and furoyl can be mentioned, for example. Preferably, it is a group which forms a pharmacologically acceptable ester, and is more preferably an acetyl group.

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; or a solvent mixture of these can be mentioned. Preferably, it is an aprotic polar solvent, more preferably N,N-dimethylformamide.

The base used includes inorganic bases such as alkali metal carbonates, e.g. sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal fluorides such as sodium fluoride and potassium fluoride; organic bases such as alkali metal alkoxides, e.g. sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can be mentioned, and is preferably an alkali metal hydride, more preferably sodium hydride or potassium hydride.

Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from −78° C. to 100° C., preferably from −20° C. to 50° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 120 hours, preferably from 10 minutes to 72 hours.

Step 5 of Method A is a step to deprotect the protective group of the sulfanyl group of the compound (10) obtained in Step 4, in an inert solvent, to prepare compound (11).

This step is a deprotection step of a protective group of a sulfanyl group which is widely used in general organic synthesis, and is conducted in accordance with the procedure described in the aforementioned “Protective Groups in Organic Synthesis, 3^(rd) edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc.” and the like, or based on that procedure, and can be preferably conducted by a deprotection procedure in an inert solvent in the presence of base.

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and 2-methoxyethanol; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone and hexamethylphosphortriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; or a solvent mixture of these can be mentioned, and is preferably an alcohol, and more preferably methanol or ethanol.

The base used includes alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and lithium hydrogencarbonate; organic bases such as alkali metal alkoxides, e.g. sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal carbonates, and more preferably potassium carbonate.

Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from −78° C. to 100° C., preferably from −20° C. to 50° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally from 1 minute to 24 hours, preferably from 5 minutes to 5 hours.

Step 6 of Method A is a step to chlorosulfonylate the thiol group of the compound (11) obtained in Step 5, in an inert solvent, to prepare compound (12).

This step can be conducted in accordance with the procedure described in Journal of Organic Chemistry (J. Org. Chem.), Vol. 16, pp. 621-625 (1951) and the like, or based on that procedure.

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and 2-methoxyethanol; aprotic polar solvents such as N, N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; nitrites such as acetonitrile; esters such as methyl acetate and ethyl acetate; carboxylic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid; water; or a solvent mixture of these can be mentioned. Preferably, it is a solvent mixture of carboxylic acids and water or a solvent mixture of nitrites and water, more preferably a solvent mixture of acetic acid and water, or a solvent mixture of acetonitrile and water.

Reaction temperature varies according to the starting compound and reaction reagent, and the reaction is conducted from −78° C. to 100° C., preferably from −20° C. to 50° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally from 1 minute to 12 hours, preferably from 5 minutes to 1 hour.

Step 7 of Method A is a step to react the compound (12) obtained in Step 6 with an amine compound (13) in an inert solvent in the presence or absence of base, to prepare a compound of general formula (I).

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; nitrites such as acetonitrile; esters such as methyl acetate and ethyl acetate; or a solvent mixture of these can be mentioned. Preferably, it is an ester, more preferably ethyl acetate.

The base used includes alkali metal hydrates such as lithium hydrate, sodium hydrate and potassium hydrate; organic bases such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably organic bases, and more preferably triethylamine.

Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from −78° C. to 100° C., preferably from −20° C. to 50° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 120 hours, preferably from 10 minutes to 48 hours.

<Method B>

Step 8 of Method B is a step to hydrolyze the cyclic ketal compound (14) obtained in Method A in an inert solvent in the presence of acid, to prepare a ketone compound (15).

This step can adopt a deprotection reaction of a cyclic ketal compound which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in the aforementioned T. W. Greene, O. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the like, or based on that procedure.

Step 9 of Method B is a step to prepare a dimethylketal compound (16) with the ketone compound (15) obtained in Step 8 in an inert solvent in the presence of acid.

This step can adopt a dimethylketalation reaction (protection) of a ketone which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in the aforementioned T. W. Greene, 0. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the like, or based on that procedure.

Step 10 of Method B is a step to react the ketone compound (15) obtained in Step 8 with the compound (2) or compound (3) in an inert solvent in the presence of acid, to prepare a compound having the general formula (I).

Here, this reaction can be conducted in accordance with a similar procedure to Step 1.

Step 10′ of Method B is a step to react the dimethylketal compound (16) obtained in Step 9 with the compound (2) or compound (3) in an inert solvent in the presence of acid, to prepare a compound having the general formula (I).

Here, this reaction can be conducted in accordance with a similar procedure to Step 1′.

<Method C>

Step 11 of Method C is a step, in the case where R⁵ of the cyclic ketal compound (14) obtained in Method A or the compound having the general formula (I) obtained in Method B is a hydrogen atom, to react it with R⁵-L (17) in an inert solvent in the presence of base, to prepare a compound having the general formula (I) which is substituted with a desired R⁵.

R⁵ and L represent the same meanings as described above, and “leaving group” in the definition of L represents a group which leaves as a nucleophilic residue, and for example, halogen atoms such as a fluorine atom, chlorine atom, bromine atom and iodine atom; lower-alkane sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy; can be mentioned. Preferably, it is a halogen atom, particularly preferably an iodine atom.

The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and includes, for example, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide; nitrites such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane and heptane, preferably, ethers, ketones or aprotic polar solvents, and more preferably, tetrahydrofuran, acetone or dimethylformamide.

The base used includes alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; organic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal carbonates, and more preferably potassium carbonate.

Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from −78° C. to 150° C., preferably from −20° C. to 100° C.

Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 24 hours, preferably from 10 minutes to 5 hours.

After each of the aforementioned reactions is completed, the desired compound is collected from the reaction mixture in accordance with general procedures.

For example, the reaction mixture is neutralized as needed, and after filtration to remove insoluble matters in the case where insoluble matters exist, the reaction solution is extracted with an organic solvent such as ethyl acetate, which does not blend with water. Then after washing the reaction solution with water and the like, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate and the like, and then the solvent is evaporated to give the desired compound.

The obtained desired compound may, if necessary, be separated and purified by ordinary procedures such as recrystallization and reprecipitation, or by a procedure generally used for separation and purification of organic compounds such as appropriately combining an adsorption column chromatography method which uses silica gel, alumina or florisil of magnesium-silica type as a support; a method using a synthetic adsorbent agent such as distribution column chromatography which uses Sephadex LH-20 (produced by Pharmacia), Amberlite XAD-11 (produced by Rohm and Haas) or Diaion HP-20 (produced by Mitsubishi Chemical Corporation) as a support, a method using ion exchange chromatography, or normal phase or reverse phase column chromatography by silica gel or alkylated silica gel (preferably high performance liquid chromatography) and eluting with an appropriate eluent.

The starting compounds such as (1), (2), (3), (5), (6), (9), (13) and (17) as reactive substances of the present invention are publicly known or can easily be prepared in accordance with publicly known procedures.

The compound having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof possesses excellent activity to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction and cell activation being induced by endotoxin, and to suppress various cell responses induced by the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α. Therefore, it is useful as a medicament, especially as a prophylactic and/or therapeutic agent for various diseases which are associated with intracellular signal transduction or cell activation induced by endotoxin, and with various cell responses (for example, excess generation of inflammatory mediators such as TNF-α) which are induced by the intracellular signal transduction and cell activation. As for such medicament, a prophylactic and/or therapeutic agent for ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, sepsis, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis or leukemia can be mentioned.

In the case where the compound having the general formula (I) according to the present invention or the pharmacologically acceptable salts thereof is used as a prophylactic agent or a therapeutic agent for the aforementioned diseases, it can be mixed with excipients, diluents and the like that are themselves pharmacologically acceptable, and administered orally as a tablet, capsule, granules, powder or syrup, or administrated parenterally as an injection for subcutaneous injection, intramuscular injection or intravenous injection or as a suppository.

These pharmaceutical preparations are prepared in accordance with known processes by using additives including excipients (for example, organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives, e.g. corn starch, potato starch, α-starch or dextrin; cellulose derivatives, e.g. crystalline cellulose; gum arabic; dextran; or pullulan, and inorganic excipients such as silicate derivatives, e.g. light silicic anhydride, synthetic aluminum silicate, calcium silicate, metamagnesium aluminate; phosphates, e.g. calcium hydrogenphosphate; carbonates, e.g. calcium carbonate; salts of sulfuric acid such as calcium sulfate, can be mentioned), lubricants (for example, stearic acid, stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloid silica; waxes such as bees wax or spermaceti, boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and the aforementioned starch derivatives can be mentioned), binders (for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol and compounds similar to the aforementioned excipient can be mentioned), disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose; or chemically modified starches or celluloses such as carboxymethyl starch, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone can be mentioned), emulsifiers (for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester), stabilizers (for example, paraoxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol, benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned) and corrigents (for example, commonly used sweeteners, acidifiers or fragrances can be mentioned) or diluents.

The amount of dosage varies according to symptoms and age, and it is desirable that the compound of the present invention is administered orally or parenterally to an adult human within a lower limit of 0.01 mg/kg (preferably 0.10 mg/kg) and an upper limit of 1000 mg/kg (preferably 100 mg/kg) per day, once a day or several times in parts depending on the symptoms.

EXAMPLES

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, however, the scope of the present invention is not limited to these.

Example 1 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-364

(1a) Ethyl 8-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate

19.97 g (55.4 mmol) of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate [compound described as compound 6 in Tetrahedron Letter, Vol. 39, pp. 6139-6142 (1998)] was dissolved in 200 ml of dimethylformamide, and 9.50 g (83.1 mmol) of potassium thioacetate was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 91 hours. To the reaction solution was added ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=17:3) to give 7.15 g of the title compound as a pale brown oil (yield: 45%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.20 (2H, q, 7 Hz), 4.04-3.96 (4H, m), 2.73-2.66 (4H, m), 2.34 (3H, s), 1.87 (2H, t, J=6 Hz), 1.28 (3H, t, J=7 Hz).

(1b) Ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate

7.14 g (24.9 mmol) of ethyl 8-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (1a) was dissolved in 145 ml of methanol, and 2.58 g (18.7 mmol) of potassium carbonate was added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour and then at room temperature for 1 hour. The reaction solution was made acidic by addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 5.63 g of the title compound as a pale yellow oil (yield: 92%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.32 (1H, s), 4.21 (2H, q, 7 Hz), 4.04-3.95 (4H, m), 2.72-2.67 (2H, m), 2.59-2.57 (2H, m), 1.82 (2H, t, J=7 Hz), 1.30 (3H, t, J=7 Hz).

(1c) Ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate

To a saturated solution prepared by blowing chlorine gas into 80 ml of solution mixture of acetonitrile-water (1:1) for 20 minutes was added a solution of 5.00 g (20.5 mmol) of ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (1b) in 10 ml of acetonitrile with stirring under ice-cooling. Chlorine gas was further blown into the reaction solution for 10 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 5.83 g of the title compound as a colorless oil (yield: 92%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.30 (2H, q, 7 Hz), 4.05-3.98 (4H, m), 2.91-2.86 (2H, m), 2.71-2.69 (2H, m), 1.93 (2H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz).

(1d) Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

To a solution of 197 mg (1.35 mmol) of 2-chloro-4-fluoroaniline and 0.20 ml (1.42 mmol) of triethylamine in 5 ml of ethyl acetate was added dropwise a solution of 400 mg (1.29 mmol) of ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (1c) in 3 ml of ethyl acetate with stirring under ice-cooling, followed by stirring at room temperature for 48 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1), and the resulting solid was further washed with a mixed solution of hexane-isopropyl ether (1:1) to give 325 mg of the title compound as a white powder (yield: 60%).

Melting point 117-119° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.67 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.98 (2H, m), 6.83 (1H, s), 4.43-4.41 (1H, m), 4.26-4.01 (5H, m), 3.95-3.88 (1H, m), 2.56-2.45 (2H, m), 2.24-2.11 (1H, m), 1.88-1.80 (1H, m), 1.27 (3H, t, J=7 Hz).

Example 2 Ethyl 8-(N-phenylsulfamoyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-12)

Following the process described in Example (1d), aniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as an amorphous substance (yield: 81%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.37-7.31 (4H, m), 7.21-7.15 (1H, m), 6.95 (1H, s), 6.85-6.87 (1H, m), 4.30-4.20 (3H, m), 4.13-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48-2.41 (1H, m), 2.31 (1H, td, J=14 Hz, 3 Hz), 2.10-2.00 (1H, m), 1.86-1.80 (1H, m), 1.31 (3H, t, J=7 Hz).

Example 3 Ethyl 8-[N-(2-butylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (exemplified compound No. 1-540)

Following the process described in Example (1d), 2-butylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a colorless oil (56% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m), 2.71-2.62 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m), 1.62-1.53 (2H, m), 1.45-1.34 (2H, m), 1.26 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz).

Example 4 Ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-716)

Following the process described in Example (1d), 2-hexylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a pale yellow oil (82% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m), 2.70-2.61 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m), 1.64-1.54 (2H, m), 1.41-1.24 (6H, m), 1.26 (3H, t, J=7 Hz), 0.91-0.85 (3H, m).

Example 5 Ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-892)

Following the process described in Example (1d), 2-heptylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a pale yellow oil (87% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m), 2.69-2.61 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m), 1.64-1.54 (2H, m), 1.42-1.23 (8H, m), 1.26 (3H, t, J=7 Hz), 0.88 (3H, t, J=7 Hz).

Example 6 Ethyl 8-[N-(1H-pyrrol-1-yl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1062)

Following the process described in Example (id), 1H-pyrrol-1-ylamine was used in place of 2-chloro-4-fluoroaniline to give the title compound as a white powder (yield: 33%).

Melting point: 115-117° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 8.05 (1H, s), 6.99 (2H, t, J=2 Hz), 6.94 (1H, s), 6.17 (2H, t, J=2 Hz), 4.55-4.51 (1H, m), 4.30 (2H, q, J=7 Hz), 4.14-4.03 (3H, m), 3.98-3.89 (1H, m), 2.51-2.44 (1H, m), 2.26-2.05 (2H, m), 1.89-1.83 (1H, m), 1.35 (3H, t, J=7 Hz).

Example 7 Ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-353)

To 2.55 g (6.07 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was added 100 ml of a mixed solution of 1N hydrochloric acid-tetrahydrofuran (1:1), and the reaction solution was stirred at room temperature for 64 hours. Tetrahydrofuran was distilled off under reduced pressure, the residue was extracted by addition of ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=4:1), to give 2.19 g of the title compound as a pale brown powder (yield: 96%).

Melting point: 128-130° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69 (1H, dd, J=9 Hz, 5 Hz), 7.20 (1H, dd, J=8 Hz, 3 Hz), 7.09-7.03 (1H, m), 6.91 (2H, s), 4.68 (1H, dd, J=5 Hz, 2 Hz), 4.28-4.18 (2H, m), 3.21-3.09 (1H, m), 2.80-2.72 (1H, m), 2.57-2.49 (1H, m), 2.44-2.31 (1H, m), 1.28 (3H, t, J=7 Hz).

Example 8 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (exemplified compound No. 1-365)

100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 2 ml of toluene, and 0.04 ml (0.54 mmol) of propane-1,3-diol and 68 mg (0.27 mmol) of pyridinium p-toluenesulfonate were added thereto, followed by heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1), and the resulting solid was further washed with hexane to give 60 mg of the title compound as a white powder (yield: 51%).

Melting point: 120-121° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.36 (1H, s), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.01 (1H, dd, J=7 Hz, 2 Hz), 6.98 (1H, s), 4.45-4.39 (1H, m), 4.27-4.12 (2H, m), 4.11-3.84 (4H, m), 2.46-2.06 (4H, m), 1.92-1.67 (2H, m), 1.28 (3H, t, J=7 Hz).

Example 9 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethyl-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-426)

Following the process described in Example 8, 2,2-dimethylpropane-1,3-diol was used in place of propane-1,3-diol to give the title compound as a pale brown oil (yield: 64%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.64 (1H, dd, J=9 Hz, 5 Hz), 7.31 (1H, s), 7.13 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.94 (2H, m), 4.45-4.39 (1H, m), 4.27-4.12 (2H, m), 3.69-3.46 (4H, m), 2.42-2.11 (4H, m), 1.28 (3H, t, J=7 Hz), 1.03 (3H, s), 0.97 (3H, s).

Example 10 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dithiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-367)

100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 1 ml of dichloromethane and 0.034 ml (0.405 mmol) of ethane-1,2-dithiol and 0.025 ml (0.203 mmol) of boron trifluoride diethyl etherate were added thereto with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction solution was added a 1N aqueous sodium hydroxide solution and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting solid was washed with diethyl ether and then with hexane to give 325 mg of the title compound as a white powder (76% yield).

Melting point: 160-161° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.10 (1H, s), 7.04-6.96 (2H, m), 4.40 (1H, d, J=5 Hz), 4.25-4.10 (2H, m), 3.52-3.26 (4H, m), 2.82-2.72 (1H, m), 2.58-2.50 (1H, m), 2.33-2.24 (1H, m), 2.11-1.99 (1H, m), 1.27 (3H, t, J=7 Hz).

Example 11 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dithiaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-368)

Following the process described in Example 10, propane-1,3-dithiol was used in place of ethane-1,2-dithiol to give the title compound as an amorphous substance (72% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.40 (1H, s), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.03-6.96 (1H, m), 6.94 (1H, s), 4.51 (1H, d, J=5 Hz), 4.24-4.11 (2H, m), 3.17-3.07 (1H, m), 2.98-2.77 (3H, m), 2.61-2.51 (1H, m), 2.47-2.38 (1H, m), 2.36-2.27 (1H, m), 2.25-2.13 (1H, m), 2.12-1.95 (2H, m), 1.27 (3H, t, J=7 Hz).

Example 12 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-oxa-4-thiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-371)

Following the process described in Example 10, 2-mercapteothanol was used in place of ethane-1,2-dithiol to give the title compound as a white powder (61% yield).

Melting point: 133-134° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.06 (0.4H, s), 7.04-6.96 (2.6H, m), 4.46 (0.4H, dd, J=5 Hz, 3 Hz), 4.39-4.01 (4.6H, m), 3.23-3.06 (2H, m), 2.77-2.51 (1.6H, m), 2.45-2.36 (0.4H, m), 2.20-2.00 (2H, m), 1.27 (3H, t, J=7 Hz).

Example 13 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,1,4,4-tetraoxo-1λ⁶,4λ⁶-dithiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-369)

80 mg (0.18 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dithiaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 10 was dissolved in 2 ml of dichloromethane, 91 mg (1.08 mmol) of sodium hydrogencarbonate was added thereto and subsequently 239 mg (0.90 mmol) of m-chloroperbenzoic acid (65%) was added with stirring under ice-cooling, followed by stirring at room temperature for 5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=1:1) to give 42 mg of the title compound as a white powder (yield: 45%).

Melting point: 88-90° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.15 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.98 (2H, m), 6.92 (1H, s), 4.57 (1H, d, J=5 Hz), 4.26-4.16 (2H, m), 3.79-3.60 (4H, m), 3.14-2.98 (1H, m), 2.69-2.60 (1H, m), 2.45-2.36 (1H, m), 2.29-2.16 (1H, m), 1.28 (3H, t, J=7 Hz).

Example 14 Ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-oxaspiro[2.5]oct-4-ene-5-carboxylate (Exemplified compound No. 1-360)

50 mg (0.133 mmol) of ethyl 6-[1-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279 mmol) of n-butyllithium/hexane solution (1.58 M) was added dropwise thereto at −78° C., followed by stirring at room temperature for 4 hours. After the reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) to give 7 mg of the title compound as a yellow oil (yield: 14%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd, J=9 Hz, 5 Hz), 7.15 (1H, dd, J=8 Hz, 3 Hz), 7.07-6.91 (2H, m), 6.60 (1H, s), 4.50 (1H, d, J=4 Hz), 4.27-4.06 (2H, m), 2.98-2.92 (1H, m), 2.91-2.88 (1H, m), 2.83-2.70 (1H, m), 2.68-2.59 (1H, m), 2.21-2.07 (2H, m), 1.25 (3H, t, J=7 Hz).

Example 15 Ethyl (2S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (exemplified compound No. 1-378)

100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 69 mg (0.35 mmol) of (R)-2,3-dihydroxypropyl benzoate were dissolved in 2 ml of dichloromethane and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 μl (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate 1:1), to give 121 mg of ethyl (2R)-2-benzoyloxymethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as a pale yellow oil (yield: 81%).

Subsequently, 121 mg (0.22 mmol) of this compound was dissolved in 2 ml of a mixture of methanol-tetrahydrofuran (1:1), and to the solution was added 0.5 ml (0.50 mmol) of 1N aqueous sodium hydroxide with stirring under ice-cooling, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 41 mg of the title compound as an amorphous substance (yield: 41%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.64 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.97 (2H, m), 6.89 (0.25H, s), 6.86 (0.25H, s), 6.80 (0.25H, s), 6.78 (0.25H, s), 4.43-4.31 (1.75H, m), 4.26-4.02 (3.25H, m), 3.95-3.87 (0.75H, m), 3.85-3.77 (1H, m), 3.75-3.69 (0.25H, m), 3.68-3.59 (1H, m), 2.65-2.38 (2H, m), 2.25-2.11 (1H, m), 2.11-2.05 (0.25H, m), 2.03-1.97 (0.25H, m), 1.94-1.81 (1.5H, m), 1.26 (3H, t, J=7 Hz).

Example 16 Ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-378)

(16a) Ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate

6.1 g (16.2 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 120 ml of methanol and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane were sequentially added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 6.0 g of the title compound as a white powder (yield: 88%).

Melting point: 97-98° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.07-6.97 (3H, m), 4.41 (1H, d, J=4 Hz), 4.28-4.12 (2H, m), 3.29 (3H, s), 3.23 (3H, s), 2.47-2.38 (1H, m), 2.31-2.21 (1H, m), 2.18-2.06 (1H, m), 2.01-1.93 (1H, m), 1.28 (3H, t, J=7 Hz).

(16b) Ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

342 mg (0.81 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexen-1-carboxylate obtained in (16a) and 206 mg (1.05 mmol) of (S)-2,3-dihydroxypropyl benzoate were dissolved in 7 ml of dichloromethane, and 0.56 ml (3.15 mmol) of isopropoxytrimethylsilane and 7 μl (0.041 mmol) of trimethylsilyl trifluoromethanesulfonate were added thereto sequentially with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1), to give 410 mg of ethyl (2S)-2-benzoyloxymethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as a colorless oil (yield: 91%).

Subsequently, 410 mg (0.74 mmol) of this compound was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (1:1) and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was added thereto, followed by stirring for 15 minutes at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 293 mg of the title compound as an amorphous substance (yield: 88%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.64 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.95 (2H, m), 6.89 (0.42H, s), 6.86 (0.02H, s), 6.80 (0.02H, s), 6.78 (0.42H, s), 4.43-4.31 (1.5H, m), 4.26-4.02 (2.5H, m), 3.96-3.89 (1H, m), 3.83-3.77 (0.5H, m), 3.75-3.69 (0.5H, m), 3.68-3.59 (1H, m), 2.65-2.41 (2H, m), 2.25-2.10 (1H, m), 1.93-1.82 (1H, m), 1.77-1.67 (0.5H, br. s), 1.58 (0.5H, br. s), 1.26 (3H, t, J=7 Hz).

Example 17 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-382)

Following the process described in Example (16b), 1,4-di-O-benzoyl-D-threitol was used in place of (S)-2,3-dihydroxypropyl benzoate to give the title compound as an amorphous substance (yield: 44%).

<Alternative Procedure>

(17a) Ethyl (2R,3R)-2,3-bis(benzoyloxymethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

1.46 g (3.08 mmol) of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol obtained in Reference Example 18 was suspended in 2 ml of acetonitrile, and 0.04 ml (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate and a solution of 1.00 g (2.37 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) in 5 ml of acetonitrile were sequentially added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 1.50 g of the title compound as a pale yellow powder (yield: 92%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 8.10-8.04 (4H, m), 7.68-7.57 (3H, m), 7.49-7.44 (4H, m), 7.16 (1H, dt, J=8.0 Hz, 2.6 Hz), 7.05-7.00 (2H, m), 6.87 (1H, d, J=14.0 Hz), 4.66-4.07 (9H, m), 2.63-2.44 (2H, m), 2.25-2.19 (1H, m), 1.94 (1H, t, J=15.2 Hz), 1.19 (3H, t, J=7.0 Hz).

(17b) Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

1.50 g (2.18 mmol) of ethyl (2R,3R)-2,3-bis(benzoyloxymethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in (17a) was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (4:1), and 10 ml (10.0 mmol) of 1N aqueous sodium hydroxide was added thereto with stirring under ice-cooling, followed by stirring for 15 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 900 mg of the title compound as a white amorphous substance (yield: 86%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69-7.64 (1H, m), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.99 (2H, m), 6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m), 4.43-4.41 (1H, m), 4.27-4.09 (3.5H, m), 4.05-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29-1.24 (3H, m).

Example 18 Ethyl (2S,3S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-382)

Following the process described in Example (16b), 1,4-di-O-benzoyl-L-threitol was used in place of (S)-2,3-dihydroxypropyl benzoate to give the title compound as an amorphous substance (34% yield).

<Alternative Procedure>

Following the process described in Example 17 (alternative procedure), 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-L-threitol obtained in Reference Example 19 was used in place of 1,4-di-o-benzoyl-2,3-di-o-trimethylsilyl-D-threitol to give the title compound as an amorphous substance (yield: 73%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69-7.64 (1H, m), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.99 (2H, m), 6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m), 4.43-4.41 (1H, m) 4.27-4.09 (3.5H, m), 4.05-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29-1.24 (3H, m).

Example 19 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-meso-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-382)

200 mg (0.47 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 290 mg (0.61 mmol) of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol obtained in Reference Example 1 were dissolved in 4 ml of dichloromethane and 4 μl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 171 mg of ethyl meso-2,3-bis[(benzoyloxy)methyl]-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous substance (yield: 53%).

Subsequently, 170 mg (0.25 mmol) of this compound was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (1:1), and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was added thereto with stirring under ice-cooling, followed by stirring for 15 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:3) to give 105 mg of the title compound as an amorphous substance (yield: 89%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.64 (1H, dd, J=9 Hz, 5 Hz), 7.15 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.95 (2H, m), 6.93 (0.4H, s), 6.72 (0.6H, s), 4.49-4.33 (2.4H, m), 4.32-4.26 (0.6H, m), 4.25-4.07 (2H, m), 3.93-3.70 (4H, m), 2.69-2.58 (0.4H, m), 2.58-2.35 (3.6H, m), 2.24-2.09 (1H, m), 1.99-1.91 (0.6H, m), 1.90-1.83 (0.4H, m), 1.27 (3H, t, J=7 Hz).

Example 20 Ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-390)

300 mg (0.71 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 436 mg (1.42 mmol) of (4R,5R)-2,2-dimethyl-4,5-bis[(trimethylsilyl)oxy]methyl[1.3]dioxolane were dissolved in 12 ml of dichloromethane and 26 μl (0.142 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 90 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 90 mg of ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((4R)-2,2-dimethyl[1.3]dioxolan-4-yl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous substance (yield: 24%).

Subsequently, to 85 mg (0.163 mmol) of this compound was added 4 ml of a mixture of acetic acid-water (1:1), followed by stirring overnight at room temperature. The reaction solution was neutralized with addition of saturated aqueous sodium hydrogencarbonate, and the mixture was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 46 mg of the title compound as an amorphous substance (yield: 59%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69-7.64 (1H, m), 7.19-7.15 (1H, m), 7.06-6.98 (2H, m), 6.89-6.80 (1H, m), 4.43-4.41 (1H, m), 4.38-4.08 (4H, m), 4.03-3.95 (0.7H, m), 3.86 (0.3H, t, J=8 Hz), 3.77-3.63 (3H, m), 2.67-2.37 (3H, m), 2.22-1.84 (3H, m), 1.30-1.25 (3H, m).

Example 21 Ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((2R)-1,2,3-trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-394)

547 mg (1.07 mmol) of 1,3,4,5,7-penta-O-trimethylsilyl-D-arabitol obtained in Reference Example 2 was dissolved in 3 ml of nitromethane, to the resulting solution was added 13 μl (0.007 mmol) of trimethylsilyl trifluoromethanesulfonate and was then added 300 mg (0.71 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. A saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 151 mg of the title compound as an amorphous substance (yield: 42%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.66 (1H, dd, J=9 Hz, 5 Hz), 7.19-7.15 (1H, m), 7.10-6.99 (2H, m), 6.86 (0.5H, s), 6.82-6.80 (0.5H, m), 4.42-4.39 (1H, m), 4.28-3.65 (9H, m), 3.20-1.40 (3H, br), 2.57-2.43 (2H, m), 2.23-2.09 (1H, m), 1.92-1.82 (1H, m), 1.29-1.25 (3H, m).

Example 22 Ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((1S,2R,3R)-1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-398)

200 mg (0.47 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 434 mg (0.71 mmol) of 1,2,3,4,5,6-hexa-O-trimethylsilyl-D-mannitol were dissolved in 4 ml of dichloromethane, to the resulting solution were added sequentially 0.12 ml (0.47 mmol) of isopropoxytrimethylsilane and 4 μl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate with stirring under ice-cooling, followed by stirring overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane:methanol=10:1) to give 130 mg of the title compound as an amorphous substance (yield: 51%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.62 (1H, dd, J=9 Hz, 5 Hz), 7.22-7.12 (2H, m), 7.04-6.96 (1H, m), 6.88-6.84 (0.2H, m), 6.80-6.77 (0.4H, m), 6.76 (0.4H, s), 4.41-4.31 (1H, m), 4.25-4.03 (4H, m), 3.98-3.63 (6H, m), 2.54-2.41 (2H, m), 2.22-2.08 (1H, m), 1.92-1.81 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 23 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-386)

Following the process described in Example 19, 1,6-di-O-benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-mannitol obtained in Reference Example 3 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol to give the title compound as a white powder (yield: 11%).

Melting point: 55-56° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.20-7.13 (2H, m), 7.06-7.00 (1H, m), 6.80 (0.5H, s), 6.78 (0.5H, s), 4.38 (1H, d, J=5 Hz), 4.26-4.00 (5H, m), 3.98-3.88 (1.5H, m), 3.87-3.65 (5.5H, m), 2.78-2.56 (2H, m), 2.55-2.40 (2H, m), 2.23-2.09 (1H, m), 1.92-1.80 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 24 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (exemplified compound No. 1-418)

Following the process described in Example 19, 2-trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantan-1-carboxylate obtained in Reference Example 4 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol to give the title compound as an amorphous substance (yield: 17%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69-7.64 (1H, m), 7.52-7.51 (0.5H, m), 7.18-7.15 (1H, m), 7.08-6.99 (2.5H, m), 4.45-4.42 (1H, m), 4.31-4.05 (4H, m), 3.88-3.74 (2H, m), 3.72-3.63 (1H, m), 2.78-2.52 (1H, br), 2.48-1.97 (4H, m), 1.31-1.26 (3H, m).

Example 25 Ethyl 12-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,4,8,5-tetraoxadispiro[5.2.5.2]hexadec-10-ene-11-carboxylate (Exemplified compound No. 1-434)

100 mg (0.266 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 156 mg (0.532 mmol) of 5,5-bis[(trimethylsilyl)oxy]methyl[1.3]dioxane were dissolved in 2 ml of dichloromethane and 10 μl (0.053 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto at −78° C., followed by stirring for 30 minutes at the same temperature and then for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) and the resulting solid was further washed with isopropyl ether to give 49 mg of the title compound as a white powder (yield: 52%).

Melting point: 156-157° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.66 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.98 (2H, m), 4.83 (1H, d, J=6 Hz), 4.78 (1H, d, J=6 Hz), 4.44-4.42 (1H, m), 4.29-4.14 (2H, m), 3.87-3.70 (8H, m), 2.44-2.38 (1H, m), 2.32-2.24 (1H, m), 2.18-2.08 (2H, m), 1.28 (3H, t, J=7 Hz).

Example 26 Ethyl 3-acetylamino-9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-422)

500 mg (1.19 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 205 mg (1.54 mmol) of N-(2-hydroxy-1-hydroxymethylethyl)acetamide were dissolved in 20 ml of dichloromethane, and 0.84 ml (4.74 mmol) of isopropoxytrimethylsilane and 43 μl (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate were added sequentially with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and further for 66 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate methanol=39:1) to give 288 mg of the title compound as an amorphous substance (yield: 50%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.66 (1H, dd, J=9 Hz, 5 Hz), 7.62-7.60 (0.5H, m), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.99 (2H, m), 6.93-6.91 (0.5H, m), 6.35 (1H, br.d, J=8 Hz), 4.46-4.42 (1H, m), 4.35-4.11 (4H, m), 4.03-3.95 (1H, m), 3.82-3.70 (2H, m), 2.60-2.55 (0.5H, m), 2.48-2.01 (3H, m), 2.06 (3H, s), 1.95-1.90 (0.5H, m), 1.30 (3H, t, J=7 Hz).

Example 27 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-430)

500 mg (1.19 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 1.0 g (2.38 mmol) of 1,3-bis[(trimethylsilyl)oxy]-2,2-bis[(trimethylsilyl)oxy]methylpropane were dissolved in 10 ml dichloromethane and 10 μl (0.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 510 mg of the title compound as an amorphous substance (yield: 87%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.66 (1H, dd, J=9 Hz, 5 Hz), 7.28 (1H, s), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.11 (1H, s), 7.07-6.98 (1H, m), 4.42 (1H, d, J=4 Hz), 4.30-4.10 (2H, m), 3.92-3.68 (8H, m), 2.54-2.36 (3H, m), 2.34-2.23 (1H, m), 2.21-2.07 (2H, m), 1.28 (3H, t, J=7 Hz).

Example 28 Triethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-3,3,8-tricarboxylate (Exemplified compound No. 1-438)

Following the process described in Example 27, diethyl 2,2-bis[(trimethylsilyl)oxy]methylmalonate obtained in Reference Example 5 was used in place of 1,3-bis[(trimethylsilyl)oxy]-2,2-bis[(trimethylsilyl)oxy]methylpropane to give the title compound as an amorphous substance (yield: 42%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.65 (1H, dd, J=9 Hz, 5 Hz), 7.23-7.21 (1H, m), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.99 (1H, m), 6.97 (1H, s), 4.43-4.36 (3H, m), 4.31-4.13 (8H, m), 2.44-2.37 (1H, m), 2.33-2.25 (1H, m), 2.19-2.06 (2H, m), 1.283 (3H, t, J=7 Hz), 1.280 (6H, t, J=7 Hz).

Example 29 Ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate (Exemplified compound No. 1-355)

(29a) Ethyl 3-[1-(2-ethoxycarbonylethyl)cyclopropyl]propionate

24.5 ml (24.5 mmol) of 1.0 M diethyl zinc/hexane solution was added to 30 ml of dichloromethane, and then a solution of 1.89 ml (24.5 mmol) of trifluoroacetic acid in 10 ml of dichloromethane was added with stirring under ice-cooling. The reaction solution was stirred for 20 minutes at the same temperature, then a solution of 1.97 ml (24.5 mmol) of diiodomethane in 10 ml of dichloromethane was added and stirred for 20 minutes, and 1.40 g (6.13 mmol) of a solution of diethyl 4-methyleneheptanedicarboxylate (compound described in J.A.C.S. 107, 13, 3981-3997 (1985)) in 10 ml of dichloromethane was further added. After the reaction solution was stirred for 6 hours at room temperature, ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=5:1) to give 1.48 g of the title compound as a brown oil (yield: 99%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.10 (2H, q, J=7 Hz), 3.37-2.31 (4H, m), 1.60-1.53 (4H, m), 1.25 (6H, t, J=7 Hz), 0.31 (4H, s).

(29b) Ethyl 6-hydroxyspiro[2.5]oct-5-ene-5-carboxylate

1.46 g (6.03 mmol) of ethyl 3-[1-(2-ethoxycarbonylethyl)cyclopropyl]propionate obtained in (29a) was dissolved in 60 ml of tetrahydrofuran and 1.35 g (12.1 mmol) of potassium t-butoxide was added thereto, followed by stirring for 1 hour at room temperature. The reaction solution was cooled with ice and made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 1.05 g of the title compound as a yellow oil (yield: 89%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 12.23 (0.7H, s), 4.26-4.09 (2H, m), 3.50 (0.3H, dd, J=10 Hz, 6 Hz), 2.57-2.42 (0.7H, m), 2.36 (2H, t, J=6 Hz), 2.03-1.94 (0.3H, m), 1.66-1.52 (1H, m), 1.48 (2H, t, J=6 Hz), 1.28 (3H, J=7 Hz), 0.60-0.30 (4H, m).

(29c) Ethyl 6-trifluoromethanesulfonyloxyspiro[2.5]oct-5-ene-5-carboxylate

1.05 g (5.35 mmol) of ethyl 6-hydroxyspiro[2.5]oct-5-ene-5-carboxylate obtained in (29b) was dissolved in 30 ml of dichloromethane, and 0.99 ml (5.89 mmol) of diisopropylethylamine and 1.40 ml (8.03 mmol) of trifluoromethanesulfonic anhydride were added sequentially with stirring at −78° C. After the reaction solution was stirred for 3 hours at the same temperature, it was warmed to room temperature. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 1.56 g of the title compound as a brown oil (yield: 89%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.26 (2H, q, J=7 Hz), 2.57-2.46 (2H, m), 2.35-2.29 (2H, m), 1.60-1.53 (2H, m), 1.32 (3H, t, J=7 Hz), 0.49-0.40 (4H, m).

(29d) Ethyl 6-mercaptospiro[2.5]oct-5-ene-5-carboxylate

Following the process described in Example (1a), ethyl 6-trifluoromethanesulfonyloxyspiro[2.5]oct-5-ene-5-carboxylate obtained in (29c) was used in place of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give ethyl 6-acetylsulfanylspiro[2.5]oct-5-ene-5-carboxylate as a pale yellow oil (yield: 58%).

Subsequently, 700 mg (2.75 mmol) of this compound was dissolved in 14 ml of ethanol, and 2.75 ml (11 mmol) of 4N hydrogen chloride/dioxane solution was added thereto with stirring under ice-cooling, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=10:1), to give 300 mg of the title compound as a pale yellow oil (yield: 51%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.19 (2H, q, J=7 Hz), 4.12 (1H, s), 2.57 (2H, t, J=6 Hz), 2.22-2.18 (2H, m), 1.46 (2H, t, J=6 Hz), 1.29 (3H, t, J=7 Hz), 0.40-0.33 (4H, m).

(29e) Ethyl 6-(chlorosulfonyl)spiro[2.5]oct-5-ene-5-carboxylate

7 ml of acetic acid was added to 651 mg (4.23 mmol) of sodium perborate tetrahydrate, the mixture was heated to 50° C., and a solution of 300 mg (1.41 mmol) of ethyl 6-mercaptospiro[2.5]oct-5-ene-5-carboxylate obtained in (29d) in 3 ml of acetic acid was added thereto, followed by stirring for 2 hours at the same temperature and further for 3 hours at 80° C. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 5 ml of thionyl chloride was added to the residue, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature again and concentrated under reduced pressure. Ice water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=5:1 to give 195 mg of the title compound as a colorless oil (yield: 50%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 4.28 (2H, q, J=7 Hz), 2.77-2.69 (2H, m), 2.43-2.38 (2H, m), 1.62 (2H, t, J=6 Hz), 1.33 (3H, t, J=7 Hz), 0.52-0.46 (4H, m).

(29f) Ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate

Following the process described in Example (1d), ethyl 6-(chlorosulfonyl)spiro[2.5]oct-5-ene-5-carboxylate obtained in (29e) was used in place of ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a white powder (yield: 17%).

Melting point: 125-126° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm: 7.69 (1H, dd, J=9 Hz, 5 Hz), 7.13 (1H, dd, J=8 Hz, 3 Hz), 7.03-6.96 (2H, m), 6.58 (1H, s), 4.53 (1H, d, J=5 Hz), 4.20-4.04 (2H, m), 2.62-2.50 (2H, m), 1.98-1.85 (1H, m), 1.23 (3H, t, J=7 Hz), 1.22-1.13 (1H, m), 1.09-0.99 (2H, m), 0.93-0.80 (2H, m).

Example 30 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity diastereomer), (high polarity diastereomer) (Exemplified compound No. 1-362)

(30a) 7-(1,3-Dioxan-2-yl)-5-[2-(1,3-dioxan-2-yl)ethyl]heptane-1,5-diol

430 mg (5 mmol) of γ-butyrolactone was dissolved in 10 ml of tetrahydrofuran, and 22 ml (11 mmol) of 0.5 M (1,3-dioxan-2-ylethyl)magnesium bromide/tetrahydrofuran solution was added thereto with stirring under ice-cooling, followed by stirring for 3 hours at 50° C. After the reaction solution was cooled with ice, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate:ethanol=10:1) to give 880 mg of the title compound as a colorless oil (yield: 55%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.51 (2H, t, J=5 Hz), 4.08 (4H, dd, J=10 Hz, 4 Hz), 3.79-3.70 (4H, m), 3.61 (2H, t, J=6 Hz), 2.13-2.00 (2H, m), 1.68-1.56 (12H, m), 1.55-1.49 (2H, m), 1.37-1.29 (2H, m).

(30b) 2-(2-{2-[2-(1,3-dioxan-2-yl)ethyl]tetrahydrofuran-2-yl}ethyl)-1,3-dioxane

2.60 g (8.17 mmol) of 7-(1,3-dioxan-2-yl)-5-[2-(1,3-dioxan-2-yl)ethyl]heptane-1,5-diol obtained in (30a) was dissolved in 45 ml of pyridine, and a solution of 1.64 g (8.58 mmol) of p-toluenesulfonyl chloride in 15 ml of pyridine was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature and further for 3 hours at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 1.31 g of the title compound as a colorless oil (yield: 53%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.50 (2H, t, J=5 Hz), 4.09 (2H, dd, J=11 Hz, 5 Hz), 3.83-3.68 (6H, m), 2.15-1.99 (2H, m), 1.92-1.82 (2H, m), 1.73-1.48 (12H, m), 1.38-1.29 (2H, m).

(30c) Ethyl 3-[2-(2-ethoxycarbonylethyl)tetrahydrofuran-2-yl]propionate

1.31 g (43.6 mmol) of 2-(2-{(2-[2-(1,3-dioxan-2-yl)ethyl]tetrahydrofuran-2-yl}ethyl)-1,3-dioxane obtained in (30b) was dissolved in 15 ml of acetone, and 16.3 ml (43.6 mmol) of Jones reagent was added thereto with stirring under ice-cooling, followed by stirring for 3 hours at room temperature. The reaction solution was cooled with ice, and then the reaction was terminated by addition of isopropyl alcohol. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was dissolved in 15 ml of ethanol, and 0.76 ml (10.5 mmol) of thionyl chloride was added, followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 610 mg of the title compound as a yellow oil (yield: 51%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.13 (4H, q, J=7 Hz), 3.78 (2H, t, J=7 Hz), 2.37-2.31 (4H, m), 1.95-1.87 (2H, m), 1.86-1.79 (4H, m) 1.71 (2H, t, J=7 Hz), 1.26 (6H, t, J=7 Hz).

(30d) Ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate

610 mg (2.24 mmol) of ethyl 3-[2-(2-ethoxycarbonylethyl)tetrahydrofuran-2-yl]propionate obtained in (30c) was dissolved in 18 ml of tetrahydrofuran, and 503 mg (4.48 mmol) of potassium t-butoxide was added thereto, followed by heating under reflux for 1 hour. After the reaction solution was cooled with ice, the reaction solution was made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 340 mg of the title compound as a colorless oil (yield: 67%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

12.24 (1H, s), 4.26-4.12 (2H, m), 3.96-3.79 (2H, m), 2.63-2.47 (1H, m), 2.43-2.12 (3H, m), 2.05-1.86 (2H, m), 1.86-1.60 (4H, m), 1.30 (3H, t, J=7 Hz).

(30e) Ethyl 8-trifluoromethanesulfonyloxy-1-oxaspiro[4.5]dec-7-ene-7-carboxylate

To a suspension of 72 mg of 55% sodium hydride (1.65 mmol)/3 ml of dichloromethane, was added a solution of 340 mg (1.50 mmol) of ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate obtained in (29d) in 4 ml of dichloromethane with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Subsequently, the reaction solution was cooled to −78° C., and 0.28 ml (1.65 mmol) of trifluoromethanesulfonic anhydride was added thereto. The mixture was stirred for 1 hour at the same temperature, and then warmed to room temperature. After ice water was added to the reaction solution to terminate the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 480 mg of the title compound as a pale yellow oil (yield: 89%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.26 (2H, q, J=7 Hz), 3.92-3.81 (2H, m), 2.74-2.63 (1H, m), 2.62-2.48 (2H, m), 2.45-2.34 (1H, m), 2.04-1.68 (6H, m), 1.32 (3H, t, J=7 Hz).

(30f) Ethyl 8-acetylthio-1-oxaspiro[4.5]dec-7-ene-7-carboxylate

Following the process described in Example (1a), ethyl 8-trifluoromethanesulfonyloxy-1-oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30e) was used in place of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a yellow oil (yield: 32%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.18 (2H, q, J=7 Hz), 3.91-3.83 (2H, m), 2.65-2.60 (1H, m), 2.60-2.51 (2H, m), 2.40-2.35 (1H, m), 2.32 (2.6H, s), 2.29 (0.4H, s), 2.00-1.93 (2H, m), 1.87-1.67 (4H, m), 1.28 (3H, t, J=7 Hz).

(30g) Ethyl 8-mercapto-1-oxaspiro[4.5]dec-7-ene-7-carboxylate

120 mg (0.42 mmol) of ethyl 8-acetylthio-1-oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was dissolved in 3 ml of ethanol, and 1 ml (4 mmol) of 4N hydrogen chloride/dioxane solution was added thereto, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) to give 100 mg of the title compound as a pale yellow oil (98% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.24-4.16 (2H, m), 4.12 (1H, s), 3.91-3.80 (2H, m), 2.84-2.71 (1H, m), 2.52-2.34 (3H, m), 2.01-1.90 (2H, m), 1.82-1.58 (4H, m), 1.23 (3H, t, J=7 Hz).

(30h) Ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7-carboxylate

100 mg (0.41 mmol) of ethyl 8-mercapto-1-oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was dissolved in 4 ml of solution mixture of acetic acid and water (acetic acid:water=1:1), and chlorine gas was blown into the reaction solution with stirring under ice-cooling for 15 minutes. Ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) to give 108 mg of the title compound as a colorless oil (yield: 85%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.28 (2H, q, J=7 Hz), 3.88 (2H, t, J=7 Hz), 2.92-2.81 (1H, m), 2.77-2.66 (1H, m), 1.58 (2H, m), 2.06-1.89 (3H, m), 1.80 (2H, t, 7 Hz), 1.77-1.67 (1H, m), 1.34 (3H, t, J=7 Hz).

(30i) Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity diastereomer), (high polarity diastereomer)

To a solution of 57 mg (0.39 mmol) of 2-chloro-4-fluoroaniline and 0.05 ml (0.39 mmol) of triethylamine in 1 ml of ethyl acetate, was added dropwise a solution of 108 mg (0.35 mmol) of ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (29h) in 2 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=3:1) to give 12 mg of low polarity diastereomer of the title compound as a white powder and 20 mg of high polarity diastereomer of the title compound as an amorphous substance (yield: 8%, 14%).

(Low Polarity Diastereomer)

Melting point: 112-114° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.65 (1H, dd, J=9 Hz, 5 Hz), 7.14 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.97 (1H, m), 6.95 (1H, s), 6.90 (1H, s), 4.45 (1H, dd, J=6 Hz, 2 Hz), 4.22-4.10 (2H, m), 3.96-3.88 (1H, m), 3.86-3.79 (1H, m), 2.41-2.33 (1H, m), 2.29-2.18 (1H, m), 2.13-2.01 (4H, m), 1.94-1.79 (2H, m), 1.25 (3H, t, J=7 Hz).

(High Polarity Diastereomer)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9 Hz, 5 Hz), 7.13 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.96 (2H, m), 6.95 (1H, s), 4.36 (1H, d, J=5 Hz), 4.22-4.10 (2H, m), 4.03-3.96 (1H, m), 3.93-3.85 (1H, m), 2.56-2.48 (1H, m), 2.40-2.29 (1H, m), 2.06-1.63 (6H, m), 1.26 (3H, t, J=7 Hz).

Example 31 Ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1057)

To a solution of 1.0 g (12.18 mmol) of 1H-pyrrol-1-ylamine and 1.8 ml (13.40 mmol) of triethylamine in 60 ml of ethyl acetate was added dropwise a solution of 3.6 g (12.18 mmol) of ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (compound disclosed in the specification of Japanese Patent Application (Kokai) No. 2000-178246) in 12 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) and the resulting solid was further washed with isopropyl ether to give 1.9 g of the title compound as a white powder (yield: 52%).

Melting point: 85-86° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.15 (1H, s), 7.44-7.42 (1H, m), 7.02 (2H, t, J=2 Hz), 6.17 (2H, t, J=2 Hz), 4.57-4.56 (1H, m), 4.29 (2H, q, J=7 Hz), 2.52-2.46 (2H, m), 2.32-2.23 (1H, m), 1.93-1.66 (3H, m), 1.34 (3H, t, J=7 Hz).

Example 32 Ethyl 6-[N-(2-methyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1176)

Following the process described in Example 31, 2-methyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 32%).

Melting point: 100-101° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.95 (1H, s), 7.43-7.39 (1H, m), 7.03-6.99 (1H, m), 6.07 (1H, t, J=4 Hz), 5.88-5.84 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J=7 Hz), 2.56-2.43 (2H, m), 2.34-2.20 (1H, m), 2.29 (3H, s), 1.95-1.66 (3H, m), 1.33 (3H, t, J=7 Hz).

Example 33 Ethyl 6-[N-(2-ethyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1193)

Following the process described in Example 31, 2-ethyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 51%).

Melting point: 77-78° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.13 (1H, t, J=4 Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.28 (2H, q, J=7 Hz), 2.79-2.64 (2H, m), 2.58-2.42 (2H, m), 2.35-2.21 (1H, m), 1.95-1.65 (3H, m), 1.33 (3H, t, J=7 Hz), 1.24 (3H, t, J=8 Hz).

Example 34 Ethyl 6-[N-(2-propyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1210)

Following the process described in Example 31, 2-propyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 31%).

Melting point: 66-68° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.12 (1H, t, J=3 Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.27 (2H, q, J=7 Hz), 2.73-2.62 (2H, m), 2.57-2.43 (2H, m), 2.34-2.21 (1H, m) 1.95-1.63 (5H, m), 1.33 (3H, t, J=7 Hz), 0.99 (3H, t, J=7 Hz).

Example 35 Ethyl 6-[N-(2-butyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1227)

Following the process described in Example 31, 2-butyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 26%).

Melting point: 49-50° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.94 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.11-6.08 (1H, m), 5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J=7 Hz), 2.71-2.65 (2H, m), 2.56-2.43 (2H, m), 2.33-2.20 (1H, m) 1.94-1.57 (5H, m), 1.45-1.35 (2H, m), 1.32 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz).

Example 36 Ethyl 6-[N-(2-pentyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1244)

Following the process described in Example 31, 2-pentyl-1H-pyrrol-1-ylamine obtained in Reference Example 6 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 33%).

Melting point: 60-61° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.12 (1H, t, J=3 Hz), 5.92-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q, J=7 Hz), 2.72-2.65 (2H, m), 2.57-2.44 (2H, m), 2.34-2.21 (1H, m), 1.95-1.59 (5H, m), 1.42-1.29 (4H, m), 1.34 (3H, t, J=7 Hz), 0.89 (3H, t, J=7 Hz).

Example 37 Ethyl 6-[N-(2-hexyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1261)

Following the process described in Example 31, 2-hexyl-1H-pyrrol-1-ylamine obtained in Reference Example 7 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a yellow oil (yield: 46%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.93 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.12-6.08 (1H, m), 5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.27 (2H, q, J=′ Hz), 2.71-2.64 (2H, m), 2.56-2.43 (2H, m), 2.33-2.21 (1H, m), 1.91-1.58 (5H, m), 1.42-1.27 (6H, m), 1.33 (3H, t, J=7 Hz), 0.88 (3H, t, J=7 Hz).

Example 38 Ethyl 6-[N-(2-heptyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1278)

Following the process described in Example 31, 2-heptyl-1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a colorless oil (yield: 13%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.11 (1H, t, J=3 Hz), 5.96-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q, J=7 Hz), 2.72-2.62 (2H, m), 2.58-2.43 (2H, m), 2.35-2.21 (1H, m), 1.94-1.59 (5H, m), 1.41-1.22 (8H, m), 1.33 (3H, t, J=7 Hz), 0.88 (3H, t, J=7 Hz).

Example 39 Ethyl 6-[N-(2-octyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1295)

Following the process described in Example 31, 2-octyl-1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale yellow oil (yield: 18%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.11 (1H, t, J=4 Hz), 5.91-5.86 (1H, m), 4.61-4.57 (1H, m), 4.28 (2H, q, J=7 Hz), 2.71-2.64 (2H, m), 2.57-2.44 (2H, m), 2.34-2.20 (1H, m), 1.95-1.58 (5H, m), 1.42-1.19 (10H, m), 1.33 (3H, t, J=7 Hz), 0.88 (3H, t, J=7 Hz).

Example 40 Ethyl 6-[N-(2-cyclopropyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1312)

Following the process described in Example 31, 2-cyclopropyl-1H-pyrrol-1-ylamine obtained in Reference Example 10 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale pink powder (yield: 42%).

Melting point: 95-96° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.87 (1H, s), 7.41-7.37 (1H, m), 6.98-6.95 (1H, m), 6.05-6.02 (1H, m), 5.69-5.66 (1H, m), 4.66-4.61 (1H, m), 4.25 (2H, q, J=7 Hz), 2.60-2.43 (2H, m), 2.34-2.20 (1H, m), 2.05-1.87 (2H, m), 1.82-1.68 (2H, m), 1.31 (3H, t, J=7 Hz), 0.94-0.82 (2H, m), 0.73-0.65 (1H, m), 0.59-0.51 (1H, m).

Example 41 Ethyl 6-[N-(2-phenyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1329)

Following the process described in Example 31, 2-phenyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale yellow powder (yield: 21%).

Melting point: 160-161° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.99 (1H, s), 7.57 (2H, d, J=8 Hz), 7.39 (2H, t, J=8 Hz), 7.33-7.27 (2H, m), 7.14-7.11 (1H, m), 6.32-6.28 (1H, m), 6.25 (1H, t, J=4 Hz), 4.22 (2H, q, J=7 Hz), 4.18-4.14 (1H, m), 2.44-2.32 (1H, m), 2.24-2.07 (2H, m), 1.91-1.75 (1H, m), 1.67-1.51 (1H, m), 1.40-1.29 (1H, m), 1.28 (3H, t, J=7 Hz).

Example 42 Ethyl 6-[N-(2,5-dimethyl-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1346)

Following the process described in Example 31, 2,5-dimethyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 29%).

Melting point: 96-97° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.88 (1H, s), 7.40-7.35 (1H, m), 5.75 (2H, s), 4.58-4.52 (1H, m), 4.24 (2H, q, 7 Hz), 2.69-2.61 (1H, m), 2.53-2.42 (1H, m), 2.33-2.19 (1H, m), 2.26 (6H, s), 2.02-1.91 (1H, m), 1.86-1.73 (2H, m), 1.30 (3H, t, J=7 Hz).

Example 43 Ethyl 6-[N-(2-chloro-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1091)

150 mg (0.503 mmol) of ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 was dissolved in 3 ml of tetrahydrofuran, and 70 mg (0.528 mmol) of N-chlorosuccinimide was added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) and the resulting solid was further washed with isopropyl ether to give 50 mg of the title compound as a white powder (yield: 30%).

Melting point: 60-61° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.91 (1H, s), 7.43-7.37 (1H, m), 7.04 (1H, dd, J=4 Hz, 2 Hz), 6.14 (1H, t, J=4 Hz), 6.10 (1H, dd, J=4 Hz, 2 Hz), 4.65-4.61 (1H, m), 4.26 (2H, q, J=7 Hz), 2.61-2.44 (2H, m), 2.33-2.21 (1H, m), 2.05-1.90 (1H, m), 1.83-1.71 (2H, m), 1.30 (3H, t, J=7 Hz).

Example 44 Ethyl 6-[N-(2-bromo-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (exemplified compound No. 1-1108)

Following the process described in Example 43, N-bromosuccinimide was used in place of N-chlorosuccinimide to give the title compound as a white powder (yield: 50%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.85 (1H, s), 7.42-7.38 (1H, m), 7.15 (1H, dd, J=4 Hz, 2 Hz), 6.22-6.17 (2H, m), 4.67-4.62 (1H, m), 4.25 (2H, q, J=7 Hz), 2.60-2.44 (2H, m), 2.33-2.20 (1H, m), 2.05-1.92 (1H, m), 1.83-1.70 (2H, m), 1.30 (3H, t, J=7 Hz).

Example 45 Ethyl 6-[N-(2,5-dichloro-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1142)

Following the process described in Example 42, 2.1 equivalent of N-chlorosuccinimide was used relative to ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 to give the title compound as a pale yellow oil (yield: 25%).

Melting point: 144-145° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.08 (1H, s), 7.39-7.33 (1H, m), 6.07 (2H, s), 4.89-4.83 (1H, m), 4.24 (2H, q, J=7 Hz), 2.67-2.58 (1H, m), 2.52-2.42 (1H, m), 2.31-2.19 (1H, m), 2.03-1.88 (1H, m), 1.87-1.72 (2H, m), 1.29 (3H, t, J=7 Hz).

Example 46 Ethyl 6-[N-(2,5-dibromo-1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate (Exemplified compound No. 1-1159)

Following the process described in Example 44, 2.1 equivalent of N-bromosuccinimide was used relative to ethyl 6-[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 to give the title compound as a white powder (yield: 3%).

Melting point: 123-124° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.05 (1H, s), 7.40-7.35 (1H, m), 6.24 (2H, s), 5.02-4.95 (1H, m), 4.25 (2H, q, J=7 Hz), 2.69-2.60 (1H, m), 2.53-2.42 (1H, m), 2.33-2.19 (1H, m), 2.02-1.90 (1H, m), 1.87-1.72 (2H, m), 1.29 (3H, t, J=7 Hz).

Example 47 t-Butyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-89)

(47a) 8-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylic acid

1.8 g (4.29 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was dissolved in 60 ml of a water-tetrahydrofuran (1:1) solution, and 900 mg (21.45 mmol) of lithium hydroxide was added thereto, followed by stirring for 7 hours at 50° C. The reaction solution was cooled with ice, it was then made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was washed with hexane to give 1.43 g of the title compound as a pale brown powder (yield: 85%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.04-6.93 (3H, m), 4.36 (1H, d, J=5 Hz), 4.16-4.02 (3H, m), 3.97-3.88 (1H, m), 2.57-2.45 (3H, m), 2.25-2.13 (1H, m), 1.90-1.82 (1H, m).

(47b) t-Butyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

100 mg (0.26 mmol) of 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylic acid obtained in (47a) was dissolved in 2 ml of toluene, and 1 ml of N,N-dimethylformamide di-t-butyl acetal was added thereto, followed by stirring for 3 hours at 100° C. After the reaction solution was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; dichloromethane:methanol=1:50) to give 52 mg of the title compound as a white amorphous substance (yield: 45%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.64 (1H, dd, J=9 Hz, 5 Hz), 7.15 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.98 (2H, m), 6.71 (1H, s), 4.42-4.38 (1H, m), 4.13-4.01 (3H, m), 3.95-3.88 (1H, m), 2.51-2.40 (2H, m), 2.21-2.10 (1H, m), 1.86-1.79 (1H, m), 1.46 (9H, s).

Following the process described in Example (47b), various corresponding acetals were used in place of N,N-dimethylformamide di-t-butyl acetal to synthesize the compounds of Examples 48 to 51.

Example 48 Methyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-73)

White powder (yield: 50%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.99 (1H, m), 6.98 (1H, s), 6.84 (1H, s), 4.43-4.38 (1H, m), 4.15-3.99 (3H, m), 3.95-3.88 (1H, m), 3.73 (3H, s), 2.56-2.43 (2H, m), 2.24-2.12 (1H, m), 1.88-1.79 (1H, m).

Example 49 Propyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-77)

White amorphous substance (yield: 18%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.97 (2H, m), 6.81 (1H, s), 4.42 (1H, d, J=5 Hz), 4.16-3.99 (5H, m), 3.95-3.88 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-1.81 (1H, m), 1.71-1.60 (2H, m), 0.94 (3H, t, J=7 Hz).

Example 50 Butyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-81)

White powder (yield: 26%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.96 (2H, m), 6.80 (1H, s), 4.42 (1H, d, J=5 Hz), 4.20-4.00 (5H, m), 3.95-3.87 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-1.80 (1H, m), 1.66-1.57 (2H, m), 1.43-1.32 (2H, m), 0.93 (3H, t, J=7 Hz).

Example 51 Isopropyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-85)

White powder (yield: 21%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.98 (2H, m), 6.78 (1H, s), 5.11-4.99 (1H, m), 4.42 (1H, d, J=5 Hz), 4.15-3.99 (3H, m), 3.95-3.88 (1H, m), 2.55-2.43 (2H, m), 2.24-2.11 (1H, m), 1.99-1.79 (1H, m), 1.26 (3H, d, J=2 Hz), 1.24 (3H, d, J=2 Hz).

Example 52 Acetoxymethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-93)

1 g (2.55 mmol) of 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylic acid obtained in Example 47a was dissolved in 20 ml of acetonitrile, and 0.50 ml (5.10 mmol) of bromomethyl acetate, 499 mg (1.53 mmol) of cesium carbonate and 471 mg (1.28 mmol) of tetrabutylammonium iodide were added thereto, followed by stirring for 1 hour at room temperature. 0.1 N hydrochloric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane:methanol=49:1) to give 833 mg of the title compound as an amorphous substance (yield: 70%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.18 (1H, dd, J=8 Hz, 3 Hz), 7.08-7.02 (1H, m), 7.01 (1H, s), 6.92 (1H, s), 5.80 (2H, s), 4.41 (1H, dd, J=6 Hz, 2 Hz), 4.15-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48 (1H, td, J=14 Hz, 4 Hz), 2.44-2.37 (1H, m), 2.22-2.14 (1H, m), 2.12 (3H, s), 1.85-1.79 (1H, m).

Following the process described in Example (1d), various corresponding anilines were used in place of 2-chloro-4-fluoroaniline to synthesize the compounds of Examples 53 to 121.

Example 53 Ethyl 8-[N-(2-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2217)

Oil (yield: 61%)

¹H-NMR spectrum (400 MHz, CDC₃) δ ppm:

7.67-7.62 (1H, m), 7.17-7.09 (3H, m), 6.96 (1H, d, J=3 Hz), 6.83 (1H, t, J=1 Hz), 4.43-4.40 (1H, m), 4.24-4.01 (5H, m), 3.95-3.89 (1H, m), 2.55-2.41 (2H, m), 2.21-2.10 (1H, m), 1.89-1.81 (1H, m), 1.27 (3H, t, J=7 Hz).

Example 54 Ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-188)

Pale brown powder (yield: 69%)

Melting point: 157-160° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.70 (1H, dd, J=8 Hz, 1 Hz), 7.39 (1H, dd, J=8 Hz, 2 Hz), 7.31-7.26 (1H, m), 7.10-7.05 (2H, m), 6.83 (1H, t, J=1 Hz), 4.49-4.46 (1H, m), 4.24-4.02 (5H, m), 3.95-3.89 (1H, m), 2.60-2.48 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7 Hz).

Example 55 Ethyl 8-[N-(2-bromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1374)

Oil (yield: 59%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.70 (1H, dd, J=8 Hz, 1 Hz), 7.55 (1H, dd, J=8 Hz, 2 Hz), 7.36-7.30 (1H, m), 7.04-6.98 (2H, m), 6.83 (1H, t, J=1 Hz), 4.50-4.47 (1H, m), 4.23-4.01 (5H, m), 3.95-3.88 (1H, m), 2.62-2.49 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7 Hz).

Example 56 Ethyl 8-[N-(2-iodophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2224)

Amorphous substance (yield: 53%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.79 (1H, dd, J=8 Hz, 1 Hz), 7.67 (1H, dd, J=8 Hz, 1 Hz), 7.38-7.33 (1H, m), 6.88-6.82 (3H, m), 4.49 (1H, d, J=5 Hz), 4.24-4.01 (5H, m), 3.95-3.88 (1H, m), 2.63-2.49 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7 Hz).

Example 57 Ethyl 8-[N-(4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-100)

White powder (yield: 87%)

Melting point: 141-146° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.38-7.33 (2H, m), 7.07-7.01 (3H, m), 6.87 (1H, t, J=1 Hz), 4.30-4.21 (3H, m), 4.14-4.01 (3H, m), 3.95-3.89 (1H, m), 2.45-2.38 (1H, m), 2.27 (1H, td, J=14 Hz, 3 Hz), 2.09-1.99 (1H, m), 1.87-1.80 (1H, m), 1.33 (3H, t, J=7 Hz).

Example 58 Ethyl 8-[N-(4-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2231)

White powder (yield: 81%)

Melting point: 153-156° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.31 (4H, s), 7.03 (1H, s), 6.87 (1H, t, J=1 Hz), 4.29-4.19 (3H, m), 4.14-4.02 (3H, m), 3.95-3.89 (1H, m), 2.47-2.40 (1H, m), 2.27 (1H, td, J=14 Hz, 3 Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H, m), 1.32 (3H, t, J=7 Hz).

Example 59 Ethyl 8-[N-(2-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2238)

White powder (yield: 75%)

Melting point: 101-104° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.56-7.53 (1H, m), 7.23-7.18 (2H, m), 7.11-7.06 (1H, m), 6.85 (1H, t, J=1 Hz), 6.62 (1H, s), 4.44 (1H, dd, J=6 Hz, 2 Hz), 4.25-4.01 (5H, m), 3.95-3.89 (1H, m), 2.55-2.48 (1H, m), 2.42 (1H, td, J=14 Hz, 4 Hz), 2.34 (3H, s), 2.19-2.09 (1H, m), 1.88-1.81 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 60 Ethyl 8-[N-(2-ethylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2245)

White powder (yield: 66%)

Melting point: 83-87° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.54 (1H, dd, J=8 Hz, 1 Hz), 7.25-7.19 (2H, m), 7.14 (1H, td, J=7 Hz, 1 Hz), 6.85 (1H, s), 6.63 (1H, s), 4.47 (1H, dd, J=6 Hz, 2 Hz), 4.25-4.02 (5H, m), 2.75-2.66 (2H, m), 2.54-2.48 (1H, m), 2.43 (1H, td, J=14 Hz, 4 Hz), 2.19-2.11 (1H, m), 1.87-1.81 (1H, m), 1.28-1.23 (6H, m).

Example 61 Ethyl 8-[N-(2-propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1989)

Oil (53% yield)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.55-7.52 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.85 (1H, t, J=1 Hz), 6.64 (1H, s), 4.48-4.44 (1H, m), 4.24-4.02 (5H, m), 3.95-3.89 (1H, m), 2.67-2.62 (2H, m), 2.54-2.39 (2H, m), 2.20-2.10 (1H, m), 1.87-1.81 (1H, m), 1.69-1.58 (2H, m), 1.26 (3H, t, J=7 Hz), 0.99 (3H, t, J=7 Hz).

Example 62 Ethyl 8-[N-(2-ethynylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2252)

Oil (yield: 19%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=8 Hz, 1 Hz), 7.47 (1H, dd, J=8 Hz, 2 Hz), 7.37 (1H, td, J=8 Hz, 2 Hz), 7.21 (1H, s), 7.07 (1H, td, J=8 Hz, 1 Hz), 6.82 (1H, t, J=1 Hz), 4.52-4.49 (1H, m), 4.22-4.01 (5H, m), 3.95-3.88 (1H, m), 3.49 (1H, s), 2.65-2.50 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.22 (3H, t, J=7 Hz).

Example 63 Ethyl 8-[N-(2-isopropylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2259)

Pale brown powder (yield: 65%)

Melting point: 115-118° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.53-7.49 (1H, m), 7.34-7.30 (1H, m), 7.23-7.17 (2H, m), 6.86 (1H, s), 6.69 (1H, s), 4.47 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.02 (5H, m), 3.95-3.89 (1H, m), 3.33-3.24 (1H, m), 2.53-2.47 (1H, m), 2.42 (1H, td, J=14 Hz, 3 Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.29-1.21 (9H, m).

Example 64 Ethyl 8-[N-(2-t-butylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2266)

White powder (yield: 53%)

Melting point: 117-120° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.45 (1H, dd, J=8 Hz, 1 Hz), 7.38 (1H, dd, J=8 Hz, 2 Hz), 7.23 (1H, td, J=8 Hz, 2 Hz), 7.12-7.07 (1H, m), 6.86 (1H, t, J=1 Hz), 6.64 (1H, s), 4.64-4.61 (1H, m), 4.24-4.03 (5H, m), 3.97-3.90 (1H, m), 2.65-2.53 (2H, m), 2.28-2.18 (1H, m), 1.90-1.83 (1H, m), 1.45 (9H, s), 1.23 (3H, t, J=7 Hz).

Example 65 Ethyl 8-[N-(2-sec-butylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2273)

Oil (71% yield)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.54-7.49 (1H, m), 7.29-7.16 (3H, m), 6.86 (1H, dt, J=5 Hz, 1 Hz), 6.68 (1H, d, J=10 Hz), 4.47-4.44 (1H, m), 4.27-4.02 (5H, m) 3.95-3.89 (1H, m), 3.12-2.95 (1H, m), 2.53-2.35 (2H, m), 2.19-2.07 (1H, m), 1.86-1.80 (1H, m), 1.70-1.55 (2H, m), 1.31-1.19 (6H, m), 0.91-0.80 (3H, m).

Example 66 Ethyl 8-[N-(2-methoxyphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2280)

White powder (yield: 70%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.57 (1H, dd, J=8 Hz, 2 Hz), 7.11-7.05 (2H, m), 6.96 (1H, td, J=8 Hz, 1 Hz), 6.89 (1H, dd, J=8 Hz, 1 Hz), 6.79 (1H, t, J=1 Hz), 4.44 (1H, d, J=4 Hz), 4.21-4.00 (5H, m), 3.94-3.84 (4H, m), 2.58 (1H, td, J=14 Hz, 4 Hz), 2.50-2.43 (1H, m), 2.18-2.08 (1H, m), 1.84-1.77 (1H, m), 1.23 (3H, t, J=7 Hz).

Example 67 Ethyl 8-[N-(2-ethoxyphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2287)

White powder (yield: 60%)

Melting point: 129-134° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.58 (1H, dd, J=8 Hz, 2 Hz), 7.12 (1H, s), 7.06 (1H, td, J=8 Hz, 2 Hz), 6.95 (1H, td, J=8 Hz, 2 Hz), 6.87 (1H, dd, J=8 Hz, 1 Hz), 6.79 (1H, t, J=1 Hz), 4.45-4.42 (1H, m), 4.20-4.00 (7H, m), 3.94-3.87 (1H, m), 2.57 (1H, td, J=14 Hz, 4 Hz), 2.50-2.44 (1H, m), 2.18-2.08 (1H, m), 1.85-1.78 (1H, m), 1.45 (3H, t, J=7 Hz), 1.23 (3H, t, J=7 Hz)

Example 68 Ethyl 8-[N-(2-difluoromethoxyphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2294)

White powder (yield: 48%)

Melting point: 85-88° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.69 (1H, dd, J=8 Hz, 2 Hz), 7.25-7.08 (4H, m), 6.84 (1H, s), 6.57 (1H, dd, J=74 Hz, 73 Hz), 4.44-4.41 (1H, m), 4.21-4.02 (5H, m), 3.95-3.89 (1H, m), 2.57-2.44 (2H, m), 2.21-2.10 (1H, m), 1.90-1.82 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 69 Ethyl 8-[N-(2-methylsulfanylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2301)

White powder (yield: 56%)

Melting point: 93-95° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.70 (1H, s), 7.63 (1H, dd, J=8 Hz, 1 Hz), 7.51 (1H, dd, J=8 Hz, 2 Hz), 7.33-7.28 (1H, m), 7.08 (1H, td, J=8 Hz, 1 Hz), 6.82 (1H, q, J=1 Hz), 4.50 (1H, d, J=4 Hz), 4.21-4.01 (5H, m), 3.95-3.88 (1H, m), 2.65-2.50 (2H, m), 2.38 (3H, s), 2.23-2.12 (1H, m), 1.88-1.81 (1H, m), 1.25-1.21 (3H, m).

Example 70 Ethyl 8-[N-(2-acetylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2308)

Oil (yield: 25%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

11.46 (1H, s), 7.91 (1H, dd, J=8 Hz, 1 Hz), 7.85 (1H, dd, J=8 Hz, 1 Hz), 7.59-7.54 (1H, m), 7.15-7.10 (1H, m), 6.80 (1H, t, J=1 Hz), 4.50-4.47 (1H, m), 4.16-4.00 (5H, m), 3.94-3.88 (1H, m), 2.68-2.59 (4H, m), 2.56-2.49 (1H, m), 2.20-2.09 (1H, m), 1.87-1.80 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 71 Ethyl 8-[N-(2-benzylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2315)

White powder (yield: 73%)

Melting point: 127-129° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.58 (1H, dd, J=8 Hz, 1 Hz), 7.32-7.13 (8H, m), 6.80 (1H, s), 6.50 (1H, s), 4.36 (1H, dd, J=6 Hz, 2 Hz), 4.23-4.00 (7H, m), 3.93-3.87 (1H, m), 2.36 (1H, td, J=14 Hz, 4 Hz), 2.19-2.13 (1H, m), 2.03-1.94 (1H, m), 1.76-1.70 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 72 Ethyl 8-{N-[2-(morpholin-4-yl)phenyl]sulfamoyl}-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2322)

White powder (yield: 71%)

Melting point: 118-121° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.10 (1H, s), 7.58 (1H, dd, J=8 Hz, 2 Hz), 7.23 (1H, dd, J=8 Hz, 2 Hz), 7.20-7.15 (1H, m), 7.07 (1H, td, J=8 Hz, 2 Hz), 6.82 (1H, t, 1 Hz), 4.47-4.44 (1H, m), 4.15-4.00 (5H, m), 3.95-3.85 (5H, m), 2.92-2.83 (4H, m), 2.59-2.50 (2H, m), 2.24-2.12 (1H, m), 1.90-1.82 (1H, m), 1.23 (3H, t, J=7 Hz).

Example 73 Ethyl 8-[N-(9H-fluoren-1-yl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2329)

Pale brown powder (yield: 60%)

Melting point: 156-160° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.78 (1H, d, J=7 Hz), 7.62 (1H, d, J=8 Hz), 7.58 (1H, d, J=7 Hz), 7.54 (1H, d, J=8 Hz), 7.42-7.37 (2H, m), 7.34 (1H, td, J=7 Hz, 1 Hz), 6.92 (1H, s), 6.86 (1H, s), 4.45 (1H, dd, J=6 Hz, 2 Hz), 4.22-4.00 (5H, m), 3.96 (2H, s), 3.94-3.89 (1H, m), 2.56-2.50 (1H, m), 2.37 (1H, td, J=14 Hz, 3 Hz), 2.17-2.08 (1H, m), 1.88-1.82 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 74 Ethyl 8-(N-{2-[2-(pyridin-4-yl)ethyl]phenyl}sulfamoyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2336)

White powder (yield: 26%)

Melting point: 77-80° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

8.50-8.47 (2H, m), 7.54-7.52 (1H, m), 7.26-7.22 (1H, m), 7.19-7.13 (4H, m), 6.89 (1H, t, J=1 Hz), 6.80 (1H, s), 4.43 (1H, dd, J=6 Hz, 3 Hz), 4.25-4.18 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 3.15-3.00 (2H, m), 2.99-2.89 (2H, m), 2.54-2.48 (1H, m), 2.33 (1H, td, J=14 Hz, 3 Hz), 2.17-2.09 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 75 Ethyl 8-(N-{2-[2-(t-butoxycarbonylamino) ethyl]phenyl}sulfamoyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2343)

Amorphous substance (yield: 65%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

8.00 (1H, s), 7.62 (1H, d, J=8 Hz), 7.24 (1H, td, J=8 Hz, 2 Hz), 7.17 (1H, d, J=7 Hz), 7.10 (1H, t, J=7 Hz), 6.83 (1H, s), 4.90 (1H, brs), 4.46 (1H, d, J=5 Hz), 4.23-4.01 (5H, m), 3.94-3.88 (1H, m), 3.27 (2H, q, J=7 Hz), 2.96-2.83 (2H, m), 2.59-2.52 (2H, m), 2.18-2.09 (1H, m), 1.83-1.78 (1H, m), 1.48-1.41 (9H, m), 1.27 (3H, t, J=7 Hz).

Example 76 Ethyl 8-[N-(2-aminophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2350)

Oil (yield: 13%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.39 (1H, dd, J=8 Hz, 2 Hz), 7.11-7.06 (1H, m), 6.89 (1H, t, J=1 Hz), 6.79-6.73 (2H, m), 4.46 (1H, dd, J=6 Hz, 3 Hz), 4.31-3.86 (3H, m), 4.28 (2H, q, J=7 Hz), 4.11-4.02 (3H, m), 3.95-3.89 (1H, m), 2.48-2.41 (1H, m), 2.24 (1H, td, J=14 Hz, 3 Hz), 2.13-2.03 (1H, m), 1.86-1.79 (1H, m), 1.32 (3H, t, J=7 Hz).

Example 77 Ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-276)

White powder (yield: 74%)

Melting point: 128-131° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.64-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (2H, m), 6.84 (1H, t, J=1 Hz), 4.36 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.02 (5H, m), 3.95-3.90 (1H, m), 2.53-2.46 (1H, m), 2.40 (1H, td, J=1-4 Hz, 4 Hz), 2.21-2.10 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 78 Ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1550)

Pale yellow powder (yield: 48%)

Melting point: 106-111° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9 Hz, 5 Hz), 7.32 (1H, dd, J=8 Hz, 3 Hz), 7.10-7.04 (1H, m), 6.94 (1H, s), 6.82 (1H, t, J=1 Hz), 4.46-4.43 (1H, m), 4.26-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.47 (2H, m), 2.24-2.13 (1H, m), 1.87-1.81 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 79 Ethyl 8-[N-(4-fluoro-2-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2357)

White powder (yield: 79%)

Melting point: 103-105° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.85 (3H, m), 6.64 (1H, brs), 4.39 (1H, dd, J=6 Hz, 3 Hz), 4.27-4.18 (2H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.52-2.45 (1H, m), 2.40-2.31 (4H, m), 2.18-2.08 (1H, m), 1.87-1.80 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 80 Ethyl 8-[N-(3-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2364)

Pale brown powder (yield: 81%)

Melting point: 111-118° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=6 Hz, 3 Hz), 7.29-7.25 (1H, m), 7.15-7.09 (2H, m), 6.88 (1H, s), 4.28 (2H, q, J=7 Hz), 4.21-4.18 (1H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.49-2.41 (1H, m), 2.25 (1H, td, J=14 Hz, 3 Hz), 2.12-2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J=7 Hz).

Example 81 Ethyl 8-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2371)

White powder (yield: 78%)

Melting point: 109-111° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.64-7.57 (2H, m), 7.27-7.17 (2H, m), 6.89 (1H, s), 4.28 (2H, q, J=7 Hz), 4.19-4.16 (1H, m), 4.14-4.03 (3H, m), 3.96-3.89 (1H, m), 2.49-2.42 (1H, m), 2.26 (1H, td, J=14 Hz, 3 Hz), 2.13-2.03 (1H, m), 1.89-1.83 (1H, m), 1.34 (3H, t, J=7 Hz).

Example 82 Ethyl 8-[N-(4-fluoro-3-methoxy phenyl)sulfamoyl]-1,4-dioxaspiro[4,5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2378)

Oil (yield: 72%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.09 (1H, dd, J=7 Hz, 2 Hz), 7.03 (1H, dd, J=11 Hz, 9 Hz), 6.96 (1H, brs), 6.88-6.83 (2H, m), 4.30-4.23 (3H, m), 4.14-4.02 (3H, m), 3.95-3.89 (4H, m), 2.46-2.38 (1H, m), 2.27 (1H, td, J=14 Hz, 3 Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J=7 Hz).

Example 83 Ethyl 8-[N-(3,4-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2385)

Pale brown powder (yield: 94%)

Melting point: 118-121° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.33-7.26 (1H, m), 7.18-7.06 (3H, m), 6.89 (1H, s), 4.28 (2H, q, J=7 Hz), 4.19 (1H, dd, J=5 Hz, 3 Hz), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.48-2.41 (1H, m), 2.25 (1H, td, J=14 Hz, 3 Hz), 2.11-2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J=7 Hz).

Example 84 Ethyl 8-[N-(2,4-dimethoxyphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2392)

White powder (yield: 49%)

Melting point: 118-121° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47-7.45 (1H, m), 6.78 (2H, d, J=9.8 Hz), 6.50-6.47 (2H, m), 4.38 (1H, d, J=4.7 Hz), 4.21-3.80 (12H, m), 2.54 (1H, dt, J=14.2 Hz, 7.2 Hz), 2.45-2.38 (1H, m), 2.14-2.08 (1H, m), 1.81-1.76 (1H, m), 1.25 (3H, t, J=7.0 Hz).

Example 85 Ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-628)

Brown oil (yield: 82%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.94 (1H, dd, J=10 Hz, 3 Hz), 6.92-6.86 (2H, m), 6.60 (1H, s), 4.41 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.18 (2H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.75-2.63 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, dt, J=14 Hz, 3 Hz), 2.18-2.08 (1H, m), 1.87-1.80 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H, m), 1.29 (3H, t, J=7 Hz), 0.95 (3H, t, J=8 Hz).

Example 86 Ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1726)

Brown oil (yield: 78%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.94 (1H, dd, J=10 Hz, 3 Hz), 6.92-6.85 (2H, m), 6.61 (1H, s), 4.40 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.18 (2H, m), 4.14-4.02 (3H, m), 3.95-3.90 (1H, m), 2.76-2.61 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, dt, J=14 Hz, 3 Hz), 2.18-2.09 (1H, m), 1.87-1.81 (1H, m), 1.65-1.52 (2H, m), 1.39-1.32 (4H, m), 1.30 (3H, t, J=7 Hz), 0.90 (3H, t, J=7 Hz).

Example 87 Ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-804)

Pale brown oil (yield: 58%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.85 (3H, m), 6.61 (1H, s), 4.40 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.18 (2H, m), 4.14-4.02 (3H, m), 3.95-3.89 (1H, m), 2.76-2.61 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, td, J=14 Hz, 3 Hz), 2.18-2.08 (1H, m), 1.87-1.81 (1H, m), 1.63-1.52 (2H, m), 1.42-1.25 (9H, m), 0.91-0.85 (3H, m).

Example 88 Ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-980)

Pale yellow oil (yield: 85%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.87 (3H, m), 6.63 (1H, s), 4.41 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.19 (2H, m), 4.14-3.91 (4H, m), 2.76-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14 Hz, 3 Hz), 2.18-2.09 (1H, m), 1.84 (1H, dt, J=13 Hz, 4 Hz), 1.62-1.55 (2H, m), 1.40-1.24 (11H, m), 0.88 (3H, t, J=7 Hz).

Example 89 Ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1902)

Pale yellow oil (yield: 72%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.87 (3H, m), 6.62 (1H, s), 4.40 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.19 (2H, m), 4.15-3.90 (4H, m), 2.74-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14 Hz, 3 Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.40-1.24 (13H, m), 0.88 (3H, t, J=7 Hz).

Example 90 Ethyl 8-[N-(4-fluoro-2-nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2602)

Pale orange oil (yield: 82%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.94 (1H, dd, J=9 Hz, 3 Hz), 6.92-6.85 (2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.17 (2H, m), 4.15-4.03 (3H, m), 3.95-3.90 (1H, m), 2.75-2.62 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, td, J=14 Hz, 3 Hz), 2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.39-1.22 (15H, m), 0.88 (3H, t, J=7 Hz).

Example 91 Ethyl 8-[N-(2-decyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2616)

Pale yellow oil (yield: 83%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.94 (1H, dd, J=9 Hz, 3 Hz), 6.92-6.85 (2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=5 Hz, 3 Hz), 4.28-4.17 (2H, m), 4.15-4.03 (3H, m), 3.95-3.90 (1H, m), 2.75-2.62 (2H, m), 2.51-2.45 (1H, m), 2.37 (1H, td, J=14 Hz, 3 Hz), 2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.39-1.22 (17H, m), 0.88 (3H, t, J=7 Hz).

Example 92 Ethyl 8-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2399)

White powder (yield: 65%)

Melting point: 130-133° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.62-7.56 (1H, m), 7.18-7.11 (2H, m), 7.02 (1H, s), 6.84 (1H, t, J=1 Hz), 4.37 (1H, dd, J=6 Hz, 2 Hz), 4.25-4.02 (5H, m), 3.96-3.89 (1H, m), 2.55-2.48 (1H, m), 2.42 (1H, td, J=14 Hz, 4 Hz), 2.21-2.11 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 93 Ethyl 8-[N-(2-bromo-4-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2406)

Pale brown powder (yield: 51%)

Melting point: 100-110° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.64 (1H, d, J=9 Hz), 7.56 (1H, d, J=3 Hz), 7.31 (1H, dd, J=9 Hz, 3 Hz), 7.02 (1H, s), 6.83 (1H, t, J=1 Hz), 4.47-4.43 (1H, m), 4.23-4.02 (5H, m), 3.95-3.89 (1H, m), 2.58-2.48 (2H, m), 2.24-2.14 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 94 Ethyl 8-[N-(4-chloro-2-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2413)

White powder (yield: 74%)

Melting point: 123-126° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, d, J=9 Hz), 4.21-4.15 (2H, m), 6.86 (1H, t, J=1 Hz), 6.65 (1H, s), 4.38 (1H, dd, J=6 Hz, 3 Hz), 4.24-4.15 (2H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.54-2.47 (1H, m), 2.41-2.32 (4H, m), 2.19-2.09 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 95 Ethyl 8-[N-(4-chloro-2-methoxycarbonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2420)

White powder (yield: 46%)

Melting point: 131-134° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

10.48 (1H, s), 8.00 (1H, d, J=3 Hz), 7.79 (1H, d, J=9 Hz), 7.50 (1H, dd, J=9 Hz, 3 Hz), 6.80 (1H, t, J=1 Hz), 4.47 (1H, dd, J=6 Hz, 2 Hz), 4.14-4.01 (5H, m), 3.95-3.88 (4H, m), 2.66-2.50 (2H, m), 2.22-2.11 (1H, m), 1.88-1.81 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 96 Ethyl 8-[N-(3,4-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2427)

White powder (yield: 66%)

Melting point: 163-164° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, d, J=2 Hz), 7.41 (1H, d, J=9 Hz), 7.23 (1H, dd, J=9 Hz, 3 Hz), 7.16 (1H, s), 6.88 (1H, t, J=1 Hz), 4.27 (2H, q, J=7 Hz), 4.21 (1H, q, J=3 Hz), 4.14-4.02 (3H, m), 3.96-3.88 (1H, m), 2.50-2.43 (1H, m), 2.27 (1H, td, J=14 Hz, 3 Hz), 2.13-2.03 (1H, m), 1.89-1.82 (1H, m), 1.33 (3H, t, J=7 Hz).

Example 97 Ethyl 8-[N-(2,5-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2434)

Pale brown powder (yield: 61%)

Melting point: 125-128° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.45-7.41 (1H, m), 7.09-7.00 (2H, m), 6.86 (1H, s), 6.80-6.74 (1H, m), 4.41 (1H, dd, J=6 Hz, 2 Hz), 4.26-4.02 (5H, m), 3.95-3.90 (1H, m), 2.58-2.52 (1H, m), 2.44 (1H, td, J=14 Hz, 3 Hz), 2.23-2.14 (1H, m), 1.89-1.84 (1H, m), 1.28 (3H, t, J=7 Hz).

Example 98 Ethyl 8-[N-(2,6-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2441)

White powder (yield: 56%)

Melting point: 129-131° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.25-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.87 (2H, m), 4.64 (1H, dd, J=5 Hz, 2 Hz), 4.31-4.21 (2H, m), 4.15-4.03 (3H, m), 3.96-3.91 (1H, m), 2.63-2.57 (1H, m), 2.36 (1H, td, J=14 Hz, 3 Hz), 2.26-2.17 (1H, m), 1.87-1.82 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 99 Ethyl 8-[N-(2-fluoro-4-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2448)

White powder (yield: 69%)

Melting point: 136-138° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.49 (1H, t, J=9 Hz), 6.95-6.92 (2H, m), 6.86 (1H, d, J=2 Hz), 6.83 (1H, s), 4.40-4.37 (1H, m), 4.26-4.15 (2H, m), 4.13-4.01 (3H, m), 3.94-3.89 (1H, m), 2.51-2.40 (2H, m), 2.32 (3H, s), 2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.27 (3H, t, J=7 Hz).

Example 100 Ethyl 8-[N-(2-fluoro-5-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2455)

Oil (yield: 63%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.43 (1H, dd, J=8 Hz, 2 Hz), 6.98 (1H, dd, J=10 Hz, 8 Hz), 6.91-6.87 (2H, m), 6.83 (1H, t, J=1 Hz), 4.42 (1H, dd, J=6 Hz, 2 Hz), 4.26-4.02 (5H, m), 3.95-3.89 (1H, m), 2.54-2.42 (2H, m), 2.20-2.12 (1H, m), 1.87-1.82 (1H, m), 1.27 (3H, t, J=7 Hz).

Example 101 Ethyl 8-[N-(2-fluoro-4-methoxyphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2462)

Pale brown powder (yield: 57%)

Melting point: 167-169° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50 (1H, t, J=9 Hz), 6.82 (1H, t, J=1 Hz), 6.79 (1H, brs), 6.71-6.67 (2H, m), 4.38-4.35 (1H, m), 4.28-4.19 (2H, m), 4.14-4.01 (3H, m), 3.95-3.88 (1H, m), 3.79 (3H, s), 2.49-2.36 (2H, m), 2.18-2.08 (1H, m), 1.86-1.79 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 102 Ethyl 8-[N-(5-chloro-2-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2469)

White powder (yield: 55%)

Melting point: 88-90° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.68-7.65 (1H, m), 7.07-7.01 (3H, m), 6.86 (1H, s), 4.40 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.15 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 2.58-2.52 (1H, m), 2.43 (1H, td, J=14 Hz, 3 Hz), 2.23-2.15 (1H, m), 1.89-1.84 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 103 Ethyl 8-[N-(2,3,4-trifluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2476)

White powder (yield: 71%)

Melting point: 149-152° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.41-7.34 (1H, m), 7.14 (1H, brs), 7.02-6.93 (1H, m), 6.85 (1H, t, J=1 Hz), 4.36 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.20 (2H, m), 4.14-4.02 (3H, m), 3.96-3.90 (1H, m), 2.55-2.46 (1H, m), 2.38 (1H, td, J=14 Hz, 4 Hz), 2.22-2.12 (1H, m), 1.89-1.82 (1H, m), 1.31 (3H, t, J=7 Hz).

Example 104 Ethyl 8-[N-(2,4,5-trifluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2483)

White powder (yield: 72%)

Melting point: 104-107° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.60-7.52 (1H, m), 7.05-6.97 (2H, m), 6.86 (1H, t, J=1 Hz), 4.35 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.19 (2H, m), 4.15-4.02 (3H, m), 3.96-3.90 (1H, m), 2.56-2.49 (1H, m), 2.38 (1H, td, J=14 Hz, 4 Hz), 2.23-2.12 (1H, m), 1.90-1.83 (1H, m), 1.30 (3H, t, J=7 Hz).

Example 105 Ethyl 8-[N-(2,4,6-trifluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2490)

White powder (yield: 61%)

Melting point: 131-133° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.91 (1H, s), 6.88 (1H, t, J=1 Hz), 6.80-6.72 (2H, m), 4.55 (1H, dd, J=6 Hz, 3 Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 2.62-2.55 (1H, m), 2.32 (1H, td, J=14 Hz, 3 Hz), 2.25-2.15 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7 Hz).

Example 106 Ethyl 8-[N-(2,4-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2497)

Pale brown powder (yield: 67%)

Melting point: 109-111° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.65 (1H, d, J=9 Hz), 7.41 (1H, d, J=2 Hz), 7.28-7.24 (1H, m), 7.07 (1H, s), 6.83 (1H, s), 4.46-4.42 (1H, m), 4.24-4.02 (5H, m), 3.98-3.89 (1H, m), 2.56-2.46 (2H, m), 2.24-2.13 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 107 Ethyl 8-[N-(4-bromo-2-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2504)

White powder (yield: 74%)

Melting point: 102-107° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.59 (1H, d, J=9 Hz), 7.55 (1H, d, J=2 Hz), 7.40 (1H, dd, J=9 Hz, 2 Hz), 7.08 (1H, s), 6.83 (1H, s), 4.44 (1H, d, J=5 Hz), 4.23-4.02 (5H, m), 3.95-3.89 (1H, m), 2.55-2.47 (2H, m), 2.23-2.14 (1H, m), 1.89-1.83 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 108 Ethyl 8-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-452)

Pale brown powder (yield: 69%)

Melting point: 130-135° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.57 (1H, d, J=9 Hz), 7.20 (1H, d, J=2 Hz), 7.10-7.06 (1H, m), 6.97 (1H, s), 6.81 (1H, d, J=1 Hz), 4.44 (1H, d, J=5 Hz), 4.25-4.00 (5H, m), 3.95-3.87 (1H, m), 2.59-2.45 (2H, m), 2.31 (3H, s), 2.22-2.10 (1H, m), 1.87-1.79 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 109 Ethyl 8-[N-(4-t-butyl-2-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2511)

Amorphous substance (yield: 49%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.61 (1H, d, J=9 Hz), 7.38 (1H, d, J=2 Hz), 7.29 (1H, dd, J=9 Hz, 2 Hz), 7.00 (1H, s), 6.82 (1H, s), 4.46 (1H, d, J=4 Hz), 4.23-4.01 (5H, m), 3.95-3.88 (1H, m), 2.59-2.47 (2H, m), 2.23-2.12 (1H, m), 1.87-1.80 (1H, m), 1.29 (9H, s), 1.25-1.21 (3H, m).

Example 110 Ethyl 8-[N-(2-chloro-6-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2518)

Amorphous substance (yield: 62%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.27-7.24 (1H, m), 7.21-7.15 (1H, m), 7.12-7.06 (1H, m), 6.98 (1H, s), 6.86 (1H, s), 4.77-4.74 (1H, m), 4.30-4.21 (2H, m), 4.15-4.03 (3H, m), 3.96-3.90 (1H, m), 2.67-2.60 (1H, m), 2.38 (1H, td, J=14 Hz, 3 Hz), 2.28-2.17 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J=7 Hz).

Example 111 Ethyl 8-[N-(2,6-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2525)

Amorphous substance (yield: 24%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.39 (1H, s), 7.38 (1H, s), 7.27 (1H, s), 7.17 (1H, t, J=8 Hz), 6.87 (1H, s), 4.88 (1H, dd, J=5 Hz, 3 Hz), 4.29 (2H, q, J=7 Hz), 4.15-4.03 (3H, m), 3.96-3.91 (1H, m), 2.68-2.62 (1H, m), 2.31 (1H, td, J=14 Hz, 3 Hz), 2.26-2.18 (1H, m), 1.88-1.82 (1H, m), 1.31 (3H, t, J=7 Hz).

Example 112 Ethyl 8-[N-(2-chloro-6-methylphenyl) sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1462)

Amorphous substance (yield: 55%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.29-7.23 (1H, m), 7.20-7.09 (3H, m), 6.84 (1H, t, J=1 Hz), 4.80-4.77 (1H, m), 4.30-4.20 (2H, m), 4.13-4.00 (3H, m), 3.95-3.89 (1H, m), 2.58-2.46 (4H, m), 2.33 (1H, td, J=14 Hz, 3 Hz), 2.25-2.14 (1H, m), 1.85-1.78 (1H, m), 1.28 (3H, t, J=7 Hz).

Example 113 Ethyl 8-[N-(2,3-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2532)

Amorphous substance (yield: 70%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.56-7.61 (1H, m), 7.26-7.19 (3H, m), 5.83 (1H, s), 4.46 (1H, d, J=5 Hz), 4.22-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.48 (2H, m), 2.25-2.14 (1H, m), 1.89-1.82 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 114 Ethyl 8-[N-(2,5-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2539)

White powder (yield: 78%)

Melting point: 120-124° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.72 (1H, d, J=2 Hz), 7.31 (1H, d, J=9 Hz), 7.11 (1H, s), 7.05 (1H, dd, J=9 Hz, 2 Hz), 6.86 (1H, s), 4.46 (1H, dd, J=6 Hz, 2 Hz), 4.25-4.03 (5H, m), 3.95-3.90 (1H, m), 2.58-2.48 (2H, m), 2.26-2.17 (1H, m), 1.90-1.84 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 115 Ethyl 8-[N-(2-chloro-4,6-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2546)

Oil (yield: 29%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.07-7.03 (1H, m), 6.99 (1H, s), 6.91-6.83 (2H, m), 4.67 (1H, dd, J=5 Hz, 3 Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.65-2.57 (1H, m), 2.34 (1H, td, J=14 Hz, 3 Hz), 2.27-2.17 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7 Hz).

Example 116 Ethyl 8-[N-(2,6-dichloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2553)

Amorphous substance (yield: 39%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.22 (1H, s), 7.17 (2H, d, J=7 Hz), 6.88 (1H, t, J=1 Hz), 4.84-4.81 (1H, m), 4.29 (2H, q, J=7 Hz), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.67-2.60 (1H, m), 2.34-2.17 (2H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J=7 Hz).

Example 117 Ethyl 8-[N-(2-bromo-6-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2560)

Amorphous substance (yield: 46%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.35 (1H, dd, J=7.5 Hz, 2.8 Hz), 7.24-7.21 (2H, m), 7.24 (1H, s), 4.90 (1H, d, J=5.1 Hz), 4.30 (2H, q, J=7.2 Hz), 4.14-3.92 (4H, m), 2.67-2.62 (1H, m), 2.33-2.18 (2H, m), 1.88-1.84 (1H, m), 1.33 (3H, t, J=6.6 Hz).

Example 118 Ethyl 8-[N-(4-chloro-2-methoxy-5-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2567)

White powder (yield: 54%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.43 (1H, s), 6.96 (1H, s), 6.87 (1H, s), 6.78 (1H, t, J=1 Hz), 4.41 (1H, dd, J=6 Hz, 2 Hz), 4.20-4.00 (5H, m), 3.94-3.88 (1H, m), 3.85 (3H, s), 2.58-2.43 (2H, m), 2.31 (3H, s), 2.20-2.08 (1H, m), 1.85-1.78 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 119 Ethyl 8-[N-(2,4-dibromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2574)

Oil (yield: 56%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.70 (1H, d, J=2 Hz), 7.59 (1H, d, J=9 Hz), 7.44 (1H, dd, J=9 Hz, 2 Hz), 7.02 (1H, s), 6.83 (1H, s), 4.47-4.44 (1H, m), 4.23-4.02 (5H, m), 3.95-3.90 (1H, m), 2.57-2.49 (2H, m), 2.23-2.15 (1H, m), 1.88-1.83 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 120 Ethyl 8-[N-(2,6-dibromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2581)

Amorphous substance (yield: 41%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.61 (2H, d, J=8 Hz), 7.26 (1H, brs), 7.02 (1H, t, J=8 Hz), 6.88 (1H, s), 5.02-5.00 (1H, m), 4.29 (2H, q, J=7 Hz), 4.15-3.91 (4H, m), 2.70-2.64 (1H, m), 2.33-2.19 (2H, m), 1.87-1.83 (1H, m), 1.32 (3H, t, J=7 Hz).

Example 121 Ethyl 8-[N-(2-bromo-4-isopropylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2588)

White powder (yield: 51%)

Melting point: 130-134° C.

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.60 (1H, d, J=8 Hz), 7.40 (1H, d, J=2 Hz), 7.18 (1H, dd, J=8 Hz, 2 Hz), 6.94 (1H, s), 6.82 (1H, s), 4.48-4.46 (1H, m), 4.24-4.01 (5H, m), 3.94-3.88 (1H, m), 2.89-2.83 (1H, m), 2.60-2.47 (2H, m), 2.22-2.13 (1H, m), 1.86-1.81 (1H, m), 1.25-1.21 (9H, m).

Example 122 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-364)

Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 1:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.1 minutes high polarity compound (second peak): 10.5 minutes (Low Polarity Compound, First Peak)

Melting point: 116-117° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9.2 Hz, 5.3 Hz), 7.17 (1H, dd, J=7.8 Hz, 2.7 Hz), 7.05-7.00 (2H, m), 6.83 (1H, s), 4.43 (1H, d, J=5.4 Hz), 4.26-3.90 (6H, m), 2.55-2.47 (2H, m), 4.15-2.47 (1H, m), 4.02-2.13 (1H, m), 1.27 (3H, t, J=7.0 Hz).

(High Polarity Compound, Second Peak)

Melting point: 116-117° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9.0 Hz, 5.5 Hz), 7.17 (1H, dd, J=8.0 Hz, 2.9 Hz), 7.06-7.00 (2H, m), 6.84 (1H, s), 4.43 (1H, d, J=5.4 Hz), 4.26-3.90 (6H, m), 2.55-2.47 (2H, m), 1.13-2.23 (1H, m), 1.87-1.83 (1H, m), 1.27 (3H, t, J=6.6 Hz).

Example 123 Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

(123a) Ethyl 7-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

Following the process described in Example (30e), ethyl 7-oxo-1,4-dioxaspiro[4.5]decane-8-carboxylate [compound disclosed as Compound 292c in US Patent application No. US2004/259914 A1] was used in place of ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate to give the title compound as a white powder (yield: 96%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.28 (2H, q, J=7 Hz), 4.04-3.96 (4H, m), 2.65-2.61 (4H, m), 1.82-1.78 (2H, m), 1.32 (3H, t, J=7 Hz).

(123b) Ethyl 7-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

Following the process described in Example (1a), ethyl 7-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123a) was used in place of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to obtain the title compound as a pale brown oil (yield: 83%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.21 (2H, q, 7 Hz), 4.04-3.96 (4H, m), 2.72-2.65 (4H, m), 2.32 (3H, s), 1.85 (2H, t, J=7 Hz), 1.29 (3H, t, J=7 Hz).

(123c) Ethyl 7-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

Following the process described in Example (1b), ethyl 7-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123b) was used in place of ethyl 8-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a pale brown powder (yield: 85%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.22 (2H, q, 7 Hz), 4.20 (1H, s), 4.02-3.95 (4H, m), 2.69-2.66 (2H, m), 2.61-2.56 (2H, m), 1.82-1.78 (2H, m), 1.30 (3H, t, J=7 Hz).

(123d) Ethyl 7-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

Following the process described in Example (1c), ethyl 7-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123c) was used in place of ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a colorless oil (yield: 62%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.31 (2H, q, 7 Hz), 4.09-4.00 (4H, m), 2.82-2.73 (4H, m), 1.86 (2H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz).

(123e) Ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

Following the process described in Example (1d), ethyl 7-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123d) was used in place of ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a white powder (yield: 61%).

Melting point: 120-122° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.81 (1H, s), 7.66 (1H, dd, J=9 Hz, 5 Hz), 7.14-7.10 (2H, m), 6.98-6.92 (1H, m), 4.71-4.67 (1H, m), 4.22-3.96 (6H, m), 2.75-2.56 (3H, m), 2.08-2.02 (1H, m), 1.24 (3H, t, J=7 Hz).

Example 124 Ethyl 2-bromoethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 1-bromo-2,3-bis[(trimethylsilyl)oxy]propane was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 100%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9.2 and 5.3 Hz), 7.17 (1H, dd, J=7.8 and 2.8 Hz), 7.05-6.99 (2H, m), 6.86-6.77 (1H, m), 4.53-3.84 (6H, m), 3.53-3.31 (2H, m), 2.66-2.41 (2H, m), 2.24-2.12 (1H, m), 1.89-1.86 (1H, m), 1.28-1.24 (3H, m).

Example 125 Ethyl (2S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-methoxycarbonylmethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), methyl (S)-3,4-bis[(trimethylsilyl)oxy]butyrate obtained in Reference Example 20 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 96%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9.0 Hz, 5.4 Hz), 7.16 (1H, dd, J=7.9 Hz, 2.8 Hz), 7.05-6.98 (2H, m), 6.88-6.76 (1H, m), 4.63-4.58 (1H, m), 4.47-4.41 (1H, m), 4.32-4.10 (3H, m), 3.84-3.59 (4H, m), 2.85-2.39 (4H, m), 2.21-2.16 (1H, m), 1.89-1.80 (1H, m), 1.29-1.24 (3H, m).

Example 126 Ethyl 3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-7,12-dioxaspiro[5.6]dodec-1-ene-2-carboxylate (Exemplified compound No. 1-366)

34 mg (0.61 mmol) of 1,4-butanediol was dissolved in 5 ml of dichloromethane, 0.32 ml (1.83 mmol) of isopropoxytrimethylsilane, and 200 mg (0.47 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 4 μl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1), and the resulting solid was further washed with hexane to give 6 mg of the title compound as a white powder (yield: 3%).

Melting point: 142-144° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9 Hz, 5 Hz), 7.16 (1H, dd, J=8 Hz, 3 Hz), 7.04 (1H, s), 7.03-6.98 (2H, m), 4.44-4.40 (1H, m), 4.27-4.11 (2H, m), 3.91-3.62 (4H, m), 2.46-2.38 (1H, m), 2.31-2.21 (1H, m), 2.17-1.94 (2H, m), 1.71-1.58 (4H, m), 1.27 (3H, t, J=7 Hz).

Example 127 Ethyl 4-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3a′,4′,6′,6a′-tetrahydrospiro[cyclohex-2-ene-1,2′-furo[3.4-d][1.3]dioxol]-3-carboxylate (Exemplified compound No. 1-402)

Following the process described in Example 21, 1,4-anhydro-2,3-di-O-trimethylsilyl-meso-erythritol obtained in Reference Example 21 was used in place of 1,3,4,5,7-penta-O-trimethylsilyl-D-arabitol to give the title compound as a white powder (yield: 56%).

Melting point: 227-228° C.

¹H-NMR spectrum (400 MHz, CDCl₃+CD₃OD) δ ppm:

7.61 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.07-6.97 (1H, m), 6.91 (1H, s), 4.93 (1H, dd, J=6 Hz, 4 Hz), 4.81 (1H, dd, J=6 Hz, 4 Hz), 4.39 (1H, d, J=5 Hz), 4.26-4.05 (3H, m), 4.01 (1H, d, J=11 Hz), 3.51-3.41 (2H, m), 2.54-2.34 (2H, m), 2.20-2.07 (1H, m), 1.90-1.79 (1H, m), 1.25 (3H, t, J=7 Hz).

Example 128 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 2,3-dimethyl-2,3-bis[(trimethylsilyl)oxy]butane was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a pale yellow oil (yield: 10%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=8.8 Hz, 5.6 Hz), 7.16 (1H, dd, J=7.8 Hz, 2.7 Hz), 7.04-7.03 (1H, m), 6.89 (1H, s), 4.37 (1H, d, J=4.0 Hz), 4.25-4.10 (2H, m), 2.51-2.43 (2H, m), 2.24-2.14 (1H, m), 1.94-1.89 (1H, m), 1.31-1.23 (15H, m).

Example 129 Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3-triethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 3-ethyl-3,4-bis[(trimethylsilyl)oxy]hexane obtained in Reference Example 22 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white powder (yield: 88%).

Melting point: 124-126° C.

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.69-7.66 (1H, m), 7.17-7.15 (1H, m), 7.04-7.00 (2H, m), 6.88-6.69 (1H, m), 4.40-4.39 (1H, m), 4.28-4.10 (2H, m), 3.90-3.68 (1H, m), 2.54-2.31 (2H, m), 2.25-2.12 (1H, m), 1.85-1.37 (7H, m), 1.29-1.24 (3H, m), 1.08-0.84 (9H, m).

Example 130 Ethyl (3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3-triphenyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), (R)-1,2-bis[(trimethylsilyl)oxy]-1,1,2-triphenylethane obtained in Reference Example 23 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 30%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.22-6.91 (20H, m), 5.99-5.76 (1H, m), 4.54-4.32 (1H, m), 4.34-4.08 (2H, m), 2.87-1.97 (4H, m), 1.36-1.14 (3H, m).

Example 131 Ethyl (2R,3R)-8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-206)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 54 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 31%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.71-7.67 (1H, m), 7.41-7.38 (1H, m), 7.32-7.26 (1H, m), 7.14-7.06 (2H, m), 6.90 (0.5H, t, J=1 Hz), 6.84 (0.5H, t, J=1 Hz), 4.47 (1H, dd, J=6 Hz, 2 Hz), 4.26-4.07 (3.5H, m), 4.05-4.00 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.67 (2H, m), 2.64-2.47 (2H, m), 2.27-1.87 (4H, m), 1.27-1.22 (3H, m).

Example 132 Ethyl (2R,3R)-8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1392)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-bromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 55 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 28%)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.71-7.67 (1H, m), 7.56 (1H, d, J=8 Hz), 7.35-7.31 (1H, m), 7.07-6.98 (2H, m), 6.90 (0.5H, s), 6.84 (0.5H, s), 4.48 (1H, d, J=5 Hz), 4.25-4.08 (3.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m), 3.76-3.68 (2H, m), 2.65-2.48 (2H, m), 2.23-1.87 (4H, m), 1.27-1.22 (3H, m).

Example 133 Ethyl (2R,3R)-2,3-bis(hydroxymethyl)-8-[N-(2-iodophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2226)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-iodophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 56 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 26%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.80 (1H, d, J=8 Hz), 7.68-7.63 (1H, m), 7.38-7.33 (1H, m), 6.90-6.83 (3H, m), 4.50-4.46 (1H, m), 4.27-4.09 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.53 (1H, brs), 2.66-2.56 (1H, m), 2.55-2.49 (1H, m), 2.24-2.14 (1H, m), 2.00-1.85 (2H, m), 1.27-1.23 (3H, m).

Example 134 Ethyl (2R,3R)-8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis (hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-734)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 4 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a colorless oil (yield: 28%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.54-7.50 (1H, m), 7.23-7.17 (2H, m), 7.15-7.09 (1H, m), 6.94-6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s), 4.48-4.43 (1H, m), 4.28-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.55-2.41 (2H, m), 2.21-2.07 (1H, m), 1.96-1.75 (3H, m), 1.64-1.52 (2H, m), 1.42-1.23 (9H, m), 0.91-0.85 (3H, m).

Example 135 Ethyl (2R,3R)-8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-910)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 5 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a colorless oil (yield: 33%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.54-7.50 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.94-6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s), 4.47-4.43 (1H, m), 4.28-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.54-2.41 (2H, m), 2.20-2.08 (1H, m), 1.96-1.74 (3H, m), 1.64-1.53 (2H, m), 1.41-1.22 (11H, m), 0.88 (3H, t, J=7 Hz).

Example 136 Ethyl (2R,3R)-8-[N-(2-chloro-4-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-470)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 108 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 50%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.56 (1H, dd, J=8 Hz, 2 Hz), 7.23-7.21 (1H, m), 7.11-7.07 (1H, m), 7.01 (1H, brs), 6.90 (0.5H, t, J=1 Hz), 6.84-6.82 (0.5H, m), 4.44 (1H, dd, J=6 Hz, 2 Hz), 4.27-4.08 (3.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.68 (2H, m), 2.63-2.44 (2H, m), 2.31 (3H, s), 2.22-1.62 (4H, m), 1.29-1.23 (3H, m).

Example 137 Ethyl (2R,3R)-8-[N-(2,4-dichlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2499)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2,4-dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 106 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 22%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.64 (1H, dd, J=9 Hz, 2 Hz), 7.41 (1H, d, J=2 Hz), 7.28-7.25 (1H, m), 7.07 (1H, brs), 6.91 (0.5H, t, J=1 Hz), 6.85 (0.5H, t, J=1 Hz), 4.43 (1H, dd, J=6 Hz, 2 Hz), 4.26-4.09 (3.5H, m), 4.07-4.02 (0.5H, m), 3.94-3.81 (2H, m), 3.77-3.68 (2H, m), 2.60-2.47 (2H, m), 2.24-1.85 (4H, m), 1.29-1.24 (3H, m).

Example 138 Ethyl (2R,3R)-8-[N-(2-bromo-4-chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2408)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-bromo-4-chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 93 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 10%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.64 (1H, dd, J=9 Hz, 3 Hz), 7.57 (1H, d, J=2 Hz), 7.31 (1H, dd, J=9 Hz, 2 Hz), 7.01 (1H, brs), 6.91 (0.5H, s), 6.85 (0.5H, s), 4.45 (1H, d, J=4 Hz), 4.26-4.10 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.82 (2H, m), 3.77-3.69 (2H, m), 2.61-2.48 (2H, m), 2.24-2.15 (1H, m), 2.02-1.85 (3H, m), 1.29-1.24 (3H, m).

Example 139 Ethyl (2R,3R)-8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1480)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 112 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 45%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.28 (1H, dd, J=8 Hz, 1 Hz), 7.23-7.07 (3H, m), 6.93-6.91 (0.5H, m), 6.86-6.85 (0.5H, m), 4.80-4.76 (1H, m), 4.30-4.17 (3H, m), 4.11-4.07 (0.5H, m), 4.04-4.00 (0.5H, m), 3.92-3.81 (2H, m), 3.75-3.69 (2H, m), 2.59-2.48 (3H, m), 2.42-2.33 (1H, m), 2.26-2.15 (1H, m), 2.07 (1H, brs), 1.94-1.85 (1H, m), 1.63 (1H, brs), 1.29-1.24 (3H, m).

Example 140 Ethyl (2R,3R)-8-[N-(3-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2366)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(3-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 80 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 47%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=6 Hz, 3 Hz), 7.29-7.25 (1H, m), 7.17-7.06 (2H, m), 6.97 (0.5H, t, J=1 Hz), 6.93-6.92 (0.5H, m), 4.33-4.09 (4.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.82 (2H, m), 3.77-3.68 (2H, m), 2.48-2.40 (1H, m), 2.34-2.24 (1H, m), 2.12-2.01 (2H, m), 1.97-1.89 (2H, m), 1.35 (3H, t, J=7 Hz).

Example 141 Ethyl (2R,3R)-8-[N-(2-chloro-4,6-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2548)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-chloro-4,6-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 115 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.07-6.85 (4H, m), 4.67 (1H, dd, J=10 Hz, 6 Hz), 4.32-4.19 (3H, m), 4.14-4.02 (1H, m), 3.93-3.82 (2H, m), 3.76-3.70 (2H, m), 2.66-2.55 (1H, m), 2.43-2.34 (1H, m), 2.28-2.17 (1H, m), 2.06-1.88 (3H, m), 1.33-1.29 (3H, m).

Example 142 Ethyl (2R,3R)-8-[N-(2,6-dichloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2555)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2,6-dichloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 116 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 25%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.26-7.05 (3H, m), 6.97-6.95 (0.5H, m), 6.90-6.89 (0.5H, m), 4.85-4.80 (1H, m), 4.33-4.19 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.02 (0.5H, m), 3.93-3.82 (2H, m), 3.76-3.70 (2H, m), 2.72-2.56 (1H, m), 2.39-2.20 (2H, m), 2.05-1.59 (3H, m), 1.35-1.30 (3H, m).

Example 143 Ethyl (2R,3R)-8-[N-(2-bromo-6-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2562)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-bromo-6-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 117 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 29%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.36-7.31 (1H, m), 7.23-7.19 (1H, m), 7.16 (1H, brs), 6.95 (0.5H, s), 6.90-6.88 (0.5H, m), 4.91-4.85 (1H, m), 4.33-4.17 (3H, m), 4.15-4.00 (1H, m), 3.94-3.80 (2H, m), 3.76-3.70 (2H, m), 3.55 (1H, brs), 2.70-2.57 (1H, m), 2.38-2.16 (2H, m), 1.96-1.87 (2H, m), 1.35-1.30 (3H, m).

Example 144 Ethyl (2R,3R)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-294)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 77 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.63-7.56 (1H, m), 7.07 (1H, brs), 6.94-6.85 (3H, m), 4.38-4.34 (1H, m), 4.30-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.81 (2H, m), 3.78-3.68 (2H, m), 2.53-2.40 (2H, m), 2.38-1.87 (4H, m), 1.31-1.27 (3H, m).

Example 145 Ethyl (2S,3S)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-294)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 77 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 58%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.37-4.34 (1H, m), 4.29-4.18 (3H, m), 4.13-4.09 (0.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.82 (2H, m), 3.76-3.69 (2H, m), 2.53-2.39 (2H, m), 2.21-1.50 (4H, m), 1.32-1.27 (3H, m).

Example 146 Ethyl (2R,3R)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1568)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 78 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 33%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.69-7.64 (1H, m), 7.33 (1H, dd, J=7 Hz, 3 Hz), 7.10-7.05 (1H, m), 6.93 (1H, brs), 6.93 (0.5H, s), 6.84 (0.5H, s), 4.44 (1H, d, J=4 Hz), 4.27-4.09 (3.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.54 (1H, brs), 2.61-2.46 (2H, m), 2.23-2.14 (1H, m), 2.02-1.85 (2H, m), 1.29-1.24 (3H, m).

Example 147 Ethyl (2S,3S)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1568)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 78 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a white amorphous substance (yield: 49%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.69-7.65 (1H, m), 7.33 (1H, dd, J=8 Hz, 3 Hz), 7.10-7.06 (1H, m), 6.99 (1H, brs), 6.91 (0.5H, s), 6.83 (0.5H, s), 4.44 (1H, d, J=4 Hz), 4.24-3.73 (8H, m), 2.61-2.48 (2H, m), 2.61-2.48 (1H, m), 1.96-1.87 (1H, m), 1.26 (3H, t, J=6 Hz).

Example 148 Ethyl (2R,3R)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-646)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 85 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 40%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.51-7.45 (1H, m), 6.97-6.85 (3H, m), 6.65 (0.5H, s), 6.59 (0.5H, s), 4.43-4.36 (1H, m), 4.29-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.07-4.01 (0.5H, m), 3.95-3.80 (2H, m), 3.77-3.68 (2H, m), 2.78-2.62 (2H, m), 2.53-2.35 (2H, m), 2.19-1.84 (4H, m), 1.65-1.49 (2H, m), 1.44-1.35 (2H, m), 1.33-1.27 (3H, m), 0.95 (3H, t, J=7 Hz).

Example 149 Ethyl (2S,3S)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-646)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 85 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 14%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.44 (1H, m), 6.98-6.86 (3H, m), 6.73 (0.4H, s), 6.68 (0.6H, s), 4.43-4.37 (1H, m), 4.26-4.16 (3H, m), 4.11-4.07 (0.4H, m), 4.05-3.99 (0.6H, m), 3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.07 (2H, m), 1.96-1.86 (1H, m), 1.63-1.53 (2H, m), 1.44-1.34 (2H, m), 1.32-1.26 (3H, m), 0.95 (3H, t, J=7 Hz).

Example 150 Ethyl (2R,3R)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1744)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 86 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 33%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.43 (1H, m), 6.97-6.85 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s), 4.42-4.37 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m), 4.05-4.01 (0.5H, m), 3.93-3.82 (2H, m), 3.76-3.68 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.80 (4H, m), 1.66-1.50 (2H, m), 1.40-1.22 (7H, m), 0.95-0.87 (3H, m).

Example 151 Ethyl (2S,3S)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1744)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 86 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 30%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.42 (1H, m), 6.97-6.84 (3H, m), 6.77 (0.5H, s), 6.72 (0.5H, s), 4.42-4.36 (1H, m), 4.30-4.14 (3H, m), 4.12-4.05 (0.5H, m), 4.04-3.98 (0.5H, m), 3.91-3.77 (2H, m), 3.76-3.67 (2H, m), 2.76-2.59 (2H, m), 2.53-2.20 (4H, m), 2.20-2.06 (1H, m), 1.97-1.84 (1H, m), 1.66-1.52 (2H, m), 1.41-1.22 (7H, m), 0.95-0.88 (3H, m).

Example 152 Ethyl (2R,3R)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-822)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 87 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 54%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.45 (1H, m), 6.96-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s), 4.41-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.36 (2H, m), 2.20-1.50 (6H, m), 1.41-1.26 (9H, m), 0.91-0.85 (3H, m).

Example 153 Ethyl (2S,3S)-8-E[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-822)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 87 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 54%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.44 (1H, m), 6.96-6.86 (3H, m), 6.70-6.67 (0.5H, m), 6.64-6.61 (0.5H, m), 4.41-4.37 (1H, m), 4.29-4.15 (3H, m), 4.12-4.07 (0.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.76-2.61 (2H, m), 2.52-2.35 (2H, m), 2.31-1.51 (6H, m), 1.40-1.26 (9H, m), 0.91-0.86 (3H, m).

Example 154 Ethyl (2R,3R)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-998)

Following the process described in Example 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 88 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 41%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, m), 6.96-6.87 (3H, m), 6.68 (0.5H, s), 6.61 (0.5H, s), 4.41-4.40 (1H, m), 4.30-3.71 (8H, m), 2.72-2.65 (2H, m), 2.48-2.39 (2H, m), 2.14-2.10 (2H, m), 1.95-1.87 (2H, m), 1.37-1.22 (11H, m), 0.88 (3H, t, J=7 Hz).

Example 155 Ethyl (2S,3S)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-998)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 88 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a white amorphous substance (yield: 70%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50, 7.48 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.70 (0.5H, s), 4.41-4.39 (1H, m), 4.28-3.71 (8H, m), 2.75-2.63 (2H, m), 2.51-2.37 (2H, m), 2.19-2.10 (2H, m), 1.95-1.88 (2H, m), 1.35-1.23 (11H, m), 0.88 (3H, t, J=7 Hz).

Example 156 Ethyl (2R,3R)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1920)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 89 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 47%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.71 (0.5H, s), 6.64 (0.5H, s), 4.41-4.39 (1H, m), 4.28-3.72 (8H, m), 2.76-2.62 (2H, m), 2.51-2.37 (2H, m), 2.18-1.89 (4H, m), 1.37-1.27 (13H, m), 0.88 (3H, t, J=7 Hz).

Example 157 Ethyl (2S,3S)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1920)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 89 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 51%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.88 (3H, m), 6.69 (0.5H, s), 6.63 (0.5H, s), 4.41-4.39 (1H, m), 4.31-3.70 (8H, m), 2.72-2.66 (2H, m), 2.52-2.37 (2H, m), 2.19-1.88 (4H, m), 1.37-1.27 (13H, m), 0.88 (3H, t, J=7 Hz).

Example 158 Ethyl (2R,3R)-8-[1N-(4-fluoro-2-nonylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2604)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(4-fluoro-2-nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 90 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 48%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.43 minutes high polarity compound (second peak): 4.73 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.66 (0.5H, s), 6.60 (0.5H, s), 4.42-4.37 (1H, m), 4.28-4.18 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m), 3.95-3.81 (2H, m), 3.76-3.69 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.99 (2H, m), 1.96-1.86 (2H, m), 1.64-1.52 (2H, m), 1.40-1.18 (15H, m), 0.91-0.85 (3H, m).

Example 159 Ethyl (2S,3S)-8-[N-(4-fluoro-2-nonylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2604)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 90 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 54%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.7 minutes high polarity compound (second peak): 10.1 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.71 (0.5H, s), 6.65 (0.5H, s), 4.42-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.01 (5H, m), 1.95-1.86 (1H, m), 1.64-1.52 (2H, m), 1.41-1.22 (15H, m), 0.88 (3H, t, J=7 Hz).

Example 160 Ethyl (2R,3R)-8-[N-(2-decyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2618)

Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2-decyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 91 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.30 minutes high polarity compound (second peak): 4.55 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.51-7.45 (1H, m), 6.97-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s), 4.42-4.36 (1H, m), 4.30-4.17 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-2.00 (2H, m), 1.99-1.86 (2H, m), 1.65-1.51 (2H, m), 1.40-1.18 (17H, m), 0.91-0.85 (3H, m).

Example 161 Ethyl (2S,3S)-8-[N-(2-decyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2618)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(2-decyl-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 91 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 56%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.4 minutes high polarity compound (second peak): 9.1 minutes

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.50-7.45 (1H, m), 6.97-6.87 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s), 4.42-4.38 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m), 4.05-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.78-3.69 (2H, m), 2.76-2.62 (2H, m), 2.52-2.37 (2H, m), 2.33-2.09 (2H, m), 2.06-1.87 (2H, m), 1.63-1.52 (2H, m), 1.40-1.22 (17H, m), 0.88 (3H, t, J=7 Hz).

Example 162 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-382)

Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 17 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 12.0 minutes high polarity compound (second peak): 16.5 minutes (Low Polarity Compound, First Peak)

Optical rotation [α]_(D)+86.7 (c=2.0, MeOH)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.07-6.98 (2H, m), 6.91 (1H, s), 4.42 (1H, dd, J=6 Hz, 2 Hz), 4.28-4.08 (4H, m), 3.91 (1H, dd, J=12 Hz, 4 Hz), 3.84 (1H, dd, J=12 Hz, 4 HZ), 3.77-3.68 (2H, m), 2.60-2.43 (2H, m), 2.26-2.11 (1H, m), 1.99-1.87 (1H, m), 1.58 (2H, bs), 1.27 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.07-6.98 (2H, m), 6.84 (1H, s), 4.42 (1H, d, J=5 Hz), 4.28-4.08 (3H, m), 4.07-4.01 (1H, m), 3.93-3.82 (2H, m), 3.77-3.68 (2H, m), 2.61-2.46 (2H, m), 2.24-2.11 (1H, m), 1.95-1.87 (1H, m), 1.57 (2H, bs), 1.27 (3H, t, J=7 Hz).

Example 163 Ethyl (2S,3S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-382)

Ethyl (2S,3S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 18 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 11.4 minutes high polarity compound (second peak): 27.4 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.06-7.00 (1H, m), 6.98 (1H, s), 6.84 (1H, s), 4.42 (1H, d, J=5 Hz), 4.27-4.09 (3H, m), 4.07-4.00 (1H, m), 3.93-3.83 (2H, m), 3.76-3.68 (2H, m), 2.60-2.47 (2H, m), 2.24-2.12 (1H, m), 1.95-1.60 (3H, m), 1.27 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.99 (2H, m), 6.90 (1H, s), 4.44-4.41 (1H, m), 4.27-4.09 (4H, m), 3.91 (1H, dd, J=12 Hz, 4 Hz), 3.84 (1H, dd, J=12 Hz, 4 HZ), 3.77-3.68 (2H, m), 2.60-2.45 (2H, m), 2.24-2.12 (1H, m), 2.00-1.65 (3H, m), 1.27 (3H, t, J=7 Hz).

Example 164 Ethyl (2R,3R)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-294)

Ethyl (2R,3R)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 144 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 13.7 minutes high polarity compound (second peak): 15.9 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, q, J=3 Hz), 4.28-4.18 (3H, m), 4.15-4.09 (1H, m), 3.91 (1H, dd, J=12 Hz, 4 Hz), 3.84 (1H, dd, J=12 Hz, 4 Hz), 3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-2.12 (1H, m), 1.96-1.90 (1H, m), 1.61 (2H, brs), 1.29 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.62-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (3H, m), 4.37-4.35 (1H, m), 4.29-4.17 (3H, m), 4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.69 (2H, m), 2.53-2.41 (2H, m), 2.20-2.11 (1H, m), 2.05 (1H, brs), 1.94-1.88 (2H, m), 1.29 (3H, t, J=7 Hz).

Example 165 Ethyl (2S,3S)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-294)

Ethyl (2S,3S)-8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 145 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.9 minutes high polarity compound (second peak): 10.7 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.36 (1H, d, J=4 Hz), 4.29-4.18 (3H, m), 4.06-4.01 (1H, m), 3.91-3.84 (2H, m), 3.75-3.70 (2H, m), 2.52-2.42 (2H, m), 2.19-1.50 (4H, m), 1.29 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, dd, J=6 Hz, 3 Hz), 4.29-4.18 (3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dd, J=12 Hz, 4 Hz), 3.84 (1H, dd, J=12 Hz, 4 Hz), 3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-1.50 (4H, m), 1.29 (3H, t, J=7 Hz).

Example 166 Ethyl (2R,3R)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1568)

Ethyl (2R,3R)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 146 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.8 minutes high polarity compound (second peak): 8.8 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9.2 Hz, 5.2 Hz), 7.34 (1H, dd, J=7.6 Hz, 2.9 Hz), 7.11-7.06 (1H, m), 6.91 (1H, s), 4.44 (1H, dd, J=5.8 Hz, 2.0 Hz), 4.28-4.10 (4H, m), 3.93-3.70 (4H, m), 2.60-2.47 (2H, m), 2.24-2.14 (1H, m), 1.97-1.92 (1H, m), 1.27 (3H, t, J=7.0 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9.2 Hz, 5.3 Hz), 7.34 (1H, dd, J=7.6 Hz, 2.9 Hz), 7.11-7.06 (1H, m), 6.85 (1H, s), 4.44 (1H, d, J=5.0 Hz), 4.27-4.02 (4H, m), 3.92-3.84 (2H, m), 3.76-3.70 (2H, m), 2.61-2.48 (2H, m), 2.23-2.15 (1H, m), 1.92-1.88 (1H, m), 1.27 (3H, t, J=7.2 Hz).

Example 167 Ethyl (2S,3S)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1568)

Ethyl (2S,3S)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 147 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 6.7 minutes high polarity compound (second peak): 13.2 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.33 (1H, dd, J=8 Hz, 3 Hz), 7.10-7.06 (1H, m), 6.84 (1H, s), 4.44 (1H, d, J=5 Hz), 4.24-3.70 (8H, m), 2.61-2.48 (2H, m), 2.24-1.87 (2H, m), 1.26 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9 Hz, 5 Hz), 7.33 (1H, dd, J=8 Hz, 3 Hz), 7.10-7.05 (1H, m), 6.91 (1H, s), 4.44 (1H, d, J=6 Hz), 4.27-3.69 (8H, m), 2.59-2.48 (2H, m), 2.23-1.91 (2H, m), 1.26 (3H, t, J=7 Hz).

Example 168 Ethyl (2R,3R)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-646)

Ethyl (2R,3R)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 148 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a pale red amorphous substance and a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 5.02 minutes high polarity compound (second peak): 5.24 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.98-6.93 (2H, m), 6.90 (1H, dt, J=8 Hz, 3 Hz), 6.67 (1H, s), 4.40 (1H, dd, J=6 Hz, 3 Hz), 4.29-4.19 (3H, m), 4.13-4.08 (1H, m), 3.92 (1H, dd, J=12 Hz, 4 Hz), 3.85 (1H, dd, 12 Hz, 4 Hz), 3.76-3.69 (2H, m), 2.78-2.62 (2H, m), 2.53-2.35 (2H, m), 2.19-1.80 (4H, m), 1.65-1.49 (2H, m), 1.44-1.34 (2H, m), 1.31 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.95 (1H, dd, J=9 Hz, 3 Hz), 6.93-6.86 (2H, m), 6.62 (1H, s), 4.41 (1H, d, J=4 Hz), 4.28-4.17 (3H, m), 4.05-4.01 (1H, m), 3.91-3.83 (2H, m), 3.77-3.69 (2H, m), 2.77-2.62 (2H, m), 2.53-2.35 (2H, m), 2.18-1.76 (4H, m), 1.65-1.50 (2H, m), 1.44-1.35 (2H, m), 1.30 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz).

Example 169 Ethyl (2S,3S)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-646)

Ethyl (2S,3S)-8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 149 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a pale red amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 5.08 minutes high polarity compound (second peak): 5.58 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=9 Hz, 5 Hz), 6.95 (1H, dd, J=9 Hz, 3 Hz), 6.93-6.86 (2H, m), 6.61 (1H, s), 4.41 (1H, d, J=4 Hz), 4.26-4.16 (3H, m), 4.05-3.99 (1H, m), 3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77-2.62 (2H, m), 2.53-2.39 (2H, m), 2.33-2.05 (2H, m), 1.96-1.86 (1H, m), 1.80-1.65 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H, m), 1.29 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.99-6.86 (3H, m), 6.70 (1H, s), 4.40 (1H, dd, J=6 Hz, 3 Hz), 4.29-4.17 (3H, m), 4.13-4.07 (1H, m), 3.90 (1H, dd, J=12 Hz, 4 Hz), 3.84 (1H, dd, 12 Hz, 4 Hz), 3.76-3.69 (2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.00 (2H, m), 1.96-1.86 (1H, m), 1.63-1.52 (2H, m), 1.44-1.34 (2H, m), 1.30 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz).

Example 170 Ethyl (2R,3R)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1744)

Ethyl (2R,3R)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 150 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a pale red amorphous substance and a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.83 minutes high polarity compound (second peak): 5.01 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.92 (2H, m), 6.90 (1H, dt, J=8 Hz, 3 Hz), 6.66 (1H, s), 4.40 (1H, dd, J=6 Hz, 3 Hz), 4.28-4.18 (3H, m), 4.14-4.07 (1H, m), 3.92 (1H, dd, J=12 Hz, 4 Hz), 3.85 (1H, dd, 12 Hz, 4 Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.50-2.35 (2H, m), 2.19-2.08 (1H, m), 1.97-1.87 (1H, m), 1.81-1.49 (4H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J=7 Hz), 0.90 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.95 (1H, dd, J=9 Hz, 3 Hz), 6.93-6.86 (2H, m), 6.60 (1H, s), 4.41 (1H, d, J=5 Hz), 4.29-4.17 (3H, m), 4.07-4.01 (1H, m), 3.93-3.84 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.54-2.36 (2H, m), 2.19-2.07 (1H, m), 2.06-1.70 (3H, m), 1.66-1.50 (2H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J=7 Hz), 0.90 (3H, t, J=7 Hz).

Example 171 Ethyl (2S,3S)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1744)

Ethyl (2S,3S)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 151 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a pale red amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purity were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.90 minutes high polarity compound (second peak): 6.18 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.85 (3H, m), 6.59 (1H, s), 4.40 (1H, d, J=5 Hz), 4.29-4.17 (3H, m), 4.06-4.00 (1H, m), 3.91-3.83 (2H, m), 3.76-3.69 (2H, m), 2.76-2.59 (2H, m), 2.53-2.36 (2H, m), 2.20-2.06 (1H, m), 1.94-1.85 (1H, m), 1.80-1.50 (4H, m), 1.41-1.22 (7H, m), 0.91 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.92 (2H, m), 6.89 (1H, dt, J=8 Hz, 3 Hz), 6.73 (1H, s), 4.40 (1H, dd, J=6 Hz, 3 Hz), 4.28-4.17 (3H, m), 4.12-4.05 (1H, m), 3.89 (1H, dd, J=12 Hz, 4 Hz), 3.82 (1H, dd, 12 Hz, 4 Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.51-2.35 (2H, m), 2.26-2.01 (2H, m), 1.97-1.68 (2H, m), 1.66-1.54 (2H, m), 1.41-1.31 (4H, m), 1.29 (3H, t, J=7 Hz), 0.90 (3H, t, J=7 Hz).

Example 172 Ethyl (2R,3R)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-822)

Ethyl (2R,3R)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 152 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 9:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 25.2 minutes high polarity compound (second peak): 29.3 minutes (Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.87 (3H, m), 6.66 (1H, s), 4.41-4.37 (1H, m), 4.29-4.19 (3H, m), 4.13-4.09 (1H, m), 3.95-3.88 (1H, m), 3.87-3.81 (1H, m), 3.77-3.69 (2H, m), 2.77-2.62 (2H, m), 2.51-2.36 (2H, m), 2.19-2.09 (2H, m), 1.95-1.89 (2H, m), 1.63-1.52 (2H, m), 1.40-1.28 (9H, m), 0.91-0.86 (3H, m).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.86 (3H, m), 6.63 (1H, s), 4.42-4.39 (1H, m), 4.30-4.16 (3H, m), 4.06-4.01 (1H, m), 3.91-3.83 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.37 (2H, m), 2.18-2.08 (2H, m), 2.03-1.98 (1H, m), 1.93-1.86 (1H, m), 1.63-1.52 (2H, m), 1.41-1.26 (9H, m), 0.91-0.86 (3H, m).

Example 173 Ethyl (2S,3S)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-822)

Ethyl (2S,3S)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 153 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purity two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 7.6 minutes high polarity compound (second peak): 10.6 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.95 (1H, dd, J=9 Hz, 3 Hz), 6.92-6.87 (2H, m), 6.61 (1H, s), 4.40 (1H, d, J=4 Hz), 4.29-4.17 (3H, m), 4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.70 (2H, m), 2.75-2.62 (2H, m), 2.52-2.46 (1H, m), 2.42 (1H, td, J=14 Hz, 3 Hz), 2.17-2.09 (1H, m), 2.05 (1H, dd, J=8 Hz, 5 Hz), 1.96-1.87 (2H, m), 1.64-1.53 (2H, m), 1.40-1.27 (9H, m), 0.91-0.87 (3H, m).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.93 (2H, m), 6.90 (1H, td, J=8 Hz, 3 Hz), 6.67 (1H, m), 4.39 (1H, dd, J=6 Hz, 4 Hz), 4.30-4.19 (3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dt, J=12 Hz, 4 Hz), 3.84 (1H, dt, J=12 Hz, 4 Hz), 3.76-3.69 (2H, m), 2.76-2.63 (2H, m), 2.50-2.44 (1H, m), 2.40 (1H, td, J=13 Hz, 3 Hz), 2.18-2.10 (2H, m), 1.95-1.89 (2H, m), 1.63-1.53 (2H, m), 1.40-1.28 (9H, m), 0.91-0.87 (3H, m).

Example 174 Ethyl (2R,3R)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Low Polarity Compound, First Peak), (High Polarity Compound, Second Peak) (Exemplified Compound No. 1-998)

Ethyl (2R,3R)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 154 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify the two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 9:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 23.9 minutes high polarity compound (second peak): 27.4 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=8 Hz, 5 Hz), 6.96-6.88 (3H, m), 6.67 (1H, s), 4.40-4.38 (1H, m), 4.27-3.69 (8H, m), 2.72-2.62 (2H, m), 2.49-1.89 (6H, m), 1.34-1.25 (11H, m), 0.88 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.47 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.87 (3H, m), 6.64 (1H, brs), 4.40 (1H, d, J=4 Hz), 4.29-3.71 (8H, m), 2.75-2.61 (2H, m), 2.51-2.37 (2H, m), 2.17-1.86 (4H, m), 1.42-1.22 (11H, m), 0.88 (3H, t, J=7 Hz).

Example 175 Ethyl (2S,3S)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Low Polarity Compound, First Peak), (High Polarity Compound, Second Peak) (Exemplified Compound No. 1-998)

Ethyl (2S,3S)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 155 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.8 minutes high polarity compound (second peak): 6.3 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.88 (3H, m), 6.64 (1H, s), 4.41 (1H, d, J=4 Hz), 4.27-3.72 (8H, m), 2.75-2.62 (2H, m), 2.51-2.38 (2H, m), 2.18-1.38 (4H, m), 1.38-1.28 (11H, m), 0.88 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.88 (3H, m), 6.69 (1H, s), 4.41-4.39 (1H, m), 4.29-3.71 (8H, m), 2.77-2.62 (2H, m), 2.49-1.90 (6H, m), 1.38-1.29 (11H, m), 0.89 (3H, t, J=7 Hz).

Example 176 Ethyl (2R,3R)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Low Polarity Compound, First Peak), (High Polarity Compound, Second Peak) (Exemplified Compound No. 1-1920)

Ethyl (2R,3R)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 156 was subjected to high performance liquid chromatography (column; CHIPALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 9:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 22.9 minutes high polarity compound (second peak): 25.8 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.96-6.88 (3H, m), 6.68 (1H, s), 6.68-4.40 (1H, m), 4.28-3.70 (8H, m), 4.28-3.70 (2H, m), 2.52-1.89 (6H, m), 1.36-1.19 (13H, m), 0.88 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.46 (1H, dd, J=9 Hz, 5 Hz), 6.95-6.87 (3H, m), 4.40 (1H, d, J=5 Hz), 4.28-3.71 (8H, m), 2.73-2.60 (2H, m), 2.50-1.87 (6H, m), 1.31-1.25 (13H, m), 0.89 (3H, t, J=7 Hz).

Example 177 Ethyl (2S,3S)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Low Polarity Compound, First Peak), (High Polarity Compound, Second Peak) (Exemplified Compound No. 1-1920)

Ethyl (2S,3S)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 157 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a colorless oil. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 4.7 minutes high polarity compound (second peak): 6.1 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.48 (1H, dd, J=9 Hz, 5 Hz), 6.97-6.88 (3H, m), 6.63 (1H, s), 4.41 (1H, d, J=5 Hz), 4.28-3.71 (8H, m), 2.75-2.62 (2H, m), 2.51-1.88 (6H, m), 1.38-1.27 (13H, m), 0.88 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=9 Hz, 6 Hz), 6.97-6.88 (3H, m), 6.97-6.88 (1H, m), 4.41-4.38 (1H, m), 4.31-3.71 (8H, m), 2.77-2.63 (2H, m), 2.50-1.90 (6H, m), 2.50-1.90 (13H, m), 0.88 (3H, t, J=7 Hz).

Example 178 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 1,4-di-O-methyl-2,3-di-O-trimethylsilyl-D-threitol was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 89%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68-7.64 (1H, m), 7.16 (1H, dd, J=8.1 Hz, 3.0 Hz), 7.17-7.16 (3H, m), 4.39 (1H, d, J=3.5 Hz), 4.24-3.98 (4H, m), 3.43-3.42 (4H, m), 3.43 (1.5H, s), 3.42 (1.5H, s), 3.39 (1.5H, s), 3.38 (1.5H, s), 2.57-2.45 (2H, m), 2.57-2.45 (1H, m), 1.96-1.86 (1H, m), 1.27 (3H, dt, J=6.9 Hz, 2.1 Hz).

Example 179 Ethyl (2S,3S)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 1,4-di-O-methyl-2,3-di-O-trimethylsilyl-L-threitol was used in place of 1,4-di-o-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (91% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68-7.64 (1H, m), 7.16 (1H, dd, J=7.8 and 2.4 Hz), 7.04-7.00 (2H, m), 6.89 (1H, s), 4.40-4.39 (1H, m), 4.23-3.97 (4H, m), 3.62-3.47 (4H, m), 3.43 (1.5H, s), 3.41 (1.5H, s), 3.39 (1.5H, s), 3.38 (1.5H, s), 2.58-2.45 (2H, m), 2.26-2.16 (1H, m), 1.96-1.86 (1H, m), 1.26 (3H, dt, J=7.0 and 3.5 Hz).

Example 180 Ethyl (2S,3S)-2,3-bis(benzyloxymethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 1,4-di-O-benzyl-2,3-di-o-trimethylsilyl-L-threitol was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 94%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.69-7.64 (1H, m), 7.37-7.26 (10H, m), 7.16 (1H, dd, J=7.8 Hz, 2.8 Hz), 7.04-6.90 (3H, m), 4.64-4.51 (4H, m), 4.40 (1H, t, J=4.5 Hz), 4.30-4.05 (4H, m), 3.68-3.57 (4H, m), 2.58-2.45 (2H, m), 2.25-2.17 (1H, m), 1.96-1.86 (1H, m), 1.21 (3H, dt, J=7.0 Hz, 3.5 Hz).

Example 181 Ethyl (2R,3R)-2,3-bis(acetoxymethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 1,4-di-O-acetyl-2,3-di-O-trimethylsilyl-D-threitol obtained in Reference Example 24 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (50% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.67 (1H, dd, J=9.2 Hz, 5.3 Hz), 7.17 (1H, dd, J=7.9 Hz, 2.8 Hz), 7.05-7.00 (2H, m), 6.90-6.76 (1H, m), 4.41 (1H, d, J=4.7 Hz), 4.37-4.37 (8H, m), 2.60-2.46 (2H, m), 2.23-2.04 (8H, m), 1.26 (3H, t, J=7.0 Hz).

Example 182 Ethyl (2S,3S)-2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-410)

218 mg (1.07 mmol) of N-(4-acetylamino-2R,3R-dihydroxybutyl)acetamide and 0.57 ml (3.20 mmol) of isopropoxytrimethylsilane were dissolved in 3 ml of nitromethane, and 13 μl (0.071 mmol) of trimethylsilyl trifluoromethanesulfonate and 300 mg (0.711 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) were sequentially added thereto with stirring under ice-cooling, followed by stirring for 3 hours at the same temperature and then for 116 hours at room temperature. To the reaction solution was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate methanol=9:1) to give 203 mg of the title compound as an amorphous substance (yield: 51%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68-7.63 (1H, m), 7.20-7.15 (1H, m), 7.08-7.00 (2H, m), 6.78-6.73 (1H, m), 6.46-6.38 (1H, m), 6.34-6.26 (1H, m), 4.42-4.39 (1H, m), 4.29-4.14 (2H, m), 3.96-3.85 (1.5H, m), 3.75-3.69 (0.5H, m), 3.61-3.42 (4H, m), 2.55-2.43 (2H, m), 2.21-2.01 (7H, m), 1.90-1.78 (1H, m), 1.31-1.25 (3H, m).

Example 183 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis((R)-1-hydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2163)

Following the process described in Example 17 (alternative procedure), (1R,2R,3R,4R)-4-benzoyloxy-1-methyl-2,3-bis[(trimethylsilyl)oxy]pentyl benzoate obtained in Reference Example 25 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 33%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.66 (1H, dd, J=9.0 and 5.0 Hz), 7.17 (1H, dd, J=7.8 and 2.7 Hz), 7.09 (1H, d, J=9.0 Hz), 7.05-7.00 (1H, m), 6.80 (0.5H, s), 6.76 (0.5H, s), 4.39 (1H, d, J=5.4 Hz), 4.27-4.09 (2H, m), 3.88-3.56 (4H, m), 2.50-2.42 (2H, m), 2.19-2.11 (1H, m), 1.85-1.79 (1H, m), 1.33 (3H, t, J=5.3 Hz), 1.27 (6H, t, J=7.0 Hz).

Example 184 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis((R)-1-hydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2164)

Following the process described in Example 17 (alternative procedure), (1R,2R,3R,4R)-4-benzoyloxy-1-ethyl-2,3-bis[(trimethylsilyl)oxy]hexyl benzoate obtained in Reference Example 26 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 21%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.68 (1H, dd, J=9.2 Hz, 5.2 Hz), 7.18 (1H, dd, J=7.4 Hz, 2.4 Hz), 7.06-7.01 (2H, m), 6.81 (0.5H, s), 6.78 (0.5H, s), 4.40 (1H, d, J=5.1 Hz), 4.29-4.12 (2H, m), 3.88-3.55 (4H, m), 3.03 (1H, brs), 2.92 (1H, brs), 2.51-2.41 (2H, m), 2.21-2.13 (2H, m), 1.90-1.73 (1H, m), 1.55-1.43 (3H, m), 1.29 (3H, t, J=7.2 Hz), 1.05-0.97 (6H, m).

Example 185 Ethyl (3a′R,6a′R,6′R)-4-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-6′-hydroxymethyl-4′-oxo-3a′,4′,6′,6a′-tetrahydrospiro[cyclohex-2-ene-1,2′-furo[3.4-d][1.3]dioxol]-3-carboxylate (Exemplified compound No. 1-2165)

Following the process described in Example (17a), (3R,4R,5R)-3,4-bis[(trimethylsilyl)oxy]-5-[(trimethylsilyl)oxy]methyldihydrofuran-2-one was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 25%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.69-7.64 (1H, m), 7.20-7.16 (1H, m), 7.06-6.96 (2H, m), 6.82-6.68 (1H, m), 5.04-4.62 (3H, m), 4.44-4.40 (1H, m), 4.26-4.14 (2H, m), 4.05-3.98 (1H, m), 3.90-3.81 (1H, m), 2.74-2.46 (2H, m), 2.24-2.12 (1H, m), 1.97-1.83 (2H, m), 1.30-1.26 (3H, m).

Example 186 Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-386)

Ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 23 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99% ee.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 7.3 minutes high polarity compound (second peak): 9.9 minutes

(Low Polarity Compound, First Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.65 (1H, dd, J=9 Hz, 5 Hz), 7.21 (1H, bs), 7.17 (1H, dd, J=8 Hz, 3 Hz), 7.06-6.99 (1H, m), 6.80 (1H, s), 4.38 (1H, d, J=5 Hz), 4.27-4.12 (4H, m), 4.08 (2H, d, J=7 Hz), 3.95-3.88 (1H, m), 3.87-3.64 (5H, m), 2.98-2.68 (2H, m), 2.54-2.42 (2H, m), 2.22-2.08 (1H, m), 1.91-1.82 (1H, m), 1.25 (3H, t, J=7 Hz).

(High Polarity Compound, Second Peak)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.63 (1H, dd, J=9 Hz, 5 Hz), 7.15 (1H, bs), 7.12 (1H, dd, J=8 Hz, 3 Hz), 7.05-6.97 (1H, m), 6.76 (1H, s), 4.37 (1H, d, J=6 Hz), 4.27-4.01 (5H, m), 3.97-3.86 (2H, m), 3.85-3.45 (5H, m), 2.77-2.57 (2H, m), 2.52-2.41 (2H, m), 2.21-2.08 (1H, m), 1.89-1.80 (1H, m), 1.26 (3H, t, J=7 Hz).

Example 187 Ethyl-(2R,3R)-8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified Compound No. 2-15)

235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 17 was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of methyl iodide and 138 mg (1.00 mmol) of potassium carbonate were added sequentially, followed by stirring for 3 hours at 50° C. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane ethyl acetate=1:3) to give 175 mg of the title compound as a white amorphous substance (yield: 73%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.57 (1H, brs), 7.22 (1H, dd, J=8 Hz, 3 Hz), 7.05-7.00 (1H, m), 6.87 (0.5H, s), 6.79 (0.5H, s), 4.58 (1H, brs), 4.28-3.73 (8H, m), 3.25 (3H, s), 2.60-1.80 (6H, m), 1.26 (3H, t, J=7 Hz).

Example 188 Ethyl 8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2077)

Following the process described in Example (id), 4-fluoro-2-propylphenylamine obtained in Reference Example 27 was used in place of 2-chloro-4-fluoroaniline to give the title compound as an oil (yield: 84%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47-7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t, J=7 Hz), 0.07 (18H, s).

Example 189 Ethyl (2S,3S)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2095)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 188 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a white amorphous substance (38% yield). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Da cel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 9.6 minutes high polarity compound (second peak): 14.1 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s), 4.42-4.39 (1H, m), 4.28-3.72 (8H, m), 2.75-2.61 (2H, m), 2.52-2.37 (2H, m), 2.19-1.87 (4H, m), 1.68-1.57 (2H, m), 1.32-1.28 (3H, m), 0.99 (3H, t, J=8 Hz).

Example 190 Ethyl (2R,3R)-2,3-bis((1R)-1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified Compound No. 1-1748)

Following the process described in Examples 7, (16a) and 23, ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 86 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as a white powder (yield: 33%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 7:3 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 5.29 minutes high polarity compound (second peak): 5.82 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49-7.44 (1H, m), 6.97-6.86 (2H, m), 6.84 (0.5H, m), 6.82 (0.5H, m), 6.73 (0.5H, s), 6.69 (0.5H, s), 4.41-4.36 (1H, m), 4.27-4.17 (2H, m), 4.12-4.01 (1.5H, m), 3.97-3.88 (1.5H, m), 3.88-3.67 (5H, m), 2.77-2.60 (2H, m), 2.50-2.30 (2H, m), 2.20-1.40 (8H, m), 1.39-1.25 (7H, m), 0.93-0.86 (3H, m).

Example 191 Ethyl (2S,3S)-8-[N-(4-fluoro-2-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2359)

Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(4-fluoro-2-methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 79 was used in place of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 49%). This compound was separable into two optical isomers in accordance with the following HPLC conditions.

HPLC conditions Column CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase hexane:2-propanol = 4:1 Flow rate 1.0 ml/min Temperature 40° C. Detection 254 nm (UV) Retention time low polarity compound (first peak): 13.5 minutes high polarity compound (second peak): 19.6 minutes

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.49 (1H, dd, J=8.8 Hz, 5.3 Hz), 6.96-6.88 (3H, m), 6.70 (0.5H, brs), 6.64 (0.5H, brs), 4.40-4.37 (1H, m), 4.28-3.70 (8H, m), 2.51-2.32 (5H, m), 2.21-1.87 (2H, m), 1.31-1.27 (3H, m).

REFERENCE EXAMPLES Reference Example 1 1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol

300 mg (0.90 mmol) of 1,4-di-O-benzoyl-meso-erythritol (compound described in J. Am. Chem. Soc., 82, 2585 (1960)), 0.28 ml (1.98 mmol) of triethylamine and 11 mg (0.09 mmol) of 4-dimethylaminopyridine were dissolved in 6 ml of dichloromethane, and 0.24 ml (1.89 mmol) of trimethylsilyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. To the reaction solution was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 418 mg of the title compound as a white powder (yield: 98%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.04 (4H, d, J=7 Hz), 7.55 (2H, t, J=7 Hz), 7.43 (4H, t, J=7 Hz), 4.53 (2H, dd, J=12 Hz, J=3 Hz), 4.36 (2H, dd, J=12 Hz, 5 Hz), 4.13-4.08 (2H, m) 0.13 (18H, s)

Reference Example 2 1,3,4,5,7-Penta-O-trimethylsilyl-D-arabitol

Following the process described in Reference Example 1, D-arabitol was used in place of 1,4-di-o-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 26%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

3.84-3.80 (1H, m), 3.76-3.68 (3H, m), 3.63-3.54 (2H, m), 3.49 (1H, dd, J=10 Hz, J=7 Hz), 0.14-0.09 (45H, m).

Reference Example 3 1,6-Di-O-benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-mannitol

Following the process described in Reference Example 1, 1,6-di-O-benzoyl-D-mannitol was used in place of 1,4-di-O-benzoyl-meso-erythritol to give the title compound as a pale brown oil (yield: 98%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.05 (4H, d, J=7 Hz), 7.55 (2H, t, J=7 Hz), 7.43 (4H, t, J=7 Hz), 4.59 (2H, dd, J=12 Hz, 2 Hz), 4.38-4.31 (2H, m), 4.24-4.20 (2H, m), 3.83 (2H, br.s), 0.17 (18H, s), 0.11 (18H, s).

Reference Example 4 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate (4a) 2-Phenyl[1.3]dioxan-5-ol adamantane-1-carboxylate

1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml (8.32 mmol) of triethylamine and 68 mg (0.56 mmol) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and then further for 15 hours at room temperature. Dichloromethane was distilled off under reduced pressure, and to the residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 1.52 g of the title compound as a pale yellow powder (yield: 80%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.52-7.48 (2H, m), 7.42-7.33 (3H, m), 5.54 (1H, s), 4.68-4.66 (1H, m), 4.26-4.22 (2H, m), 4.18-4.13 (2H, m), 2.07-2.01 (3H, m), 2.01-1.97 (6H, m), 1.77-1.69 (6H, m).

(4b) 2-Hydroxy-1-hydroxymethylethyl adamantane-1-carboxylate

400 mg (1.17 mmol) of 2-phenyl[1.3]dioxan-5-yl adamantane-1-carboxylate obtained in (4a) was dissolved in 8 ml of ethyl acetate and 400 mg of 20% palladium hydroxide-carbon (water content: 50%) was added thereto, followed by stirring for 4 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure to give 294 mg of the title compound as a white powder (yield: 99%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.90-4.85 (1H, m), 3.84-3.76 (4H, m), 2.16-2.00 (5H, m), 1.94-1.87 (6H, m), 1.78-1.67 (6H, m).

(4c) 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate

Following the process described in Reference Example 1, 2-hydroxy-1-hydroxymethylethyl adamantane-1-carboxylate obtained in (4b) was used in place of 1,4-di-O-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 70%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.85-4.79 (1H, m), 3.72-3.61 (4H, m), 2.04-1.97 (3H, m), 1.92-1.83 (6H, m), 1.76-1.65 (6H, m), 0.11 (18H, s).

Reference Example 5 Diethyl 2,2-bis[(trimethylsilyl)oxy]methylmalonate

Following the process described in Reference Example 1, diethyl 2,2-bis(hydroxymethyl)malonate was used in place of 1,4-di-O-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 75%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.17 (4H, q, J=7 Hz), 4.04 (4H, s), 1.23 (6H, t, J=7 Hz), 0.07 (18H, s).

Reference Example 6 2-Pentyl-1H-pyrrol-1-ylamine (6a) (2E)-4-Oxo-2-nonenal

2.0 g (14.47 mmol) of 2-pentylfuran was dissolved in 60 ml of dichloromethane, and 3.84 g (14.47 mmol) of 65% m-chloroperbenzoic acid was added dropwise thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. To the reaction solution was added saturated aqueous sodium carbonate and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1.62 g of the title compound as a yellow oil (yield: 73%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

10.23 (1H, d, J=7 Hz), 6.95 (1H, d, J=12 Hz), 6.18 (1H, dd, J=12 Hz, 7 Hz), 2.26 (2H, t, J=7 Hz), 1.73-1.61 (2H, m), 1.40-1.26 (4H, m), 0.91 (3H, t, J=6 Hz).

(6b) 4-Oxononanal

1.62 g (10.5 mmol) of (2E)-4-oxo-2-nonenal obtained in (6a) was dissolved in 30 ml of ethyl acetate, and 160 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by restirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure to give 1.50 g of the title compound as a pale yellow oil (91% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

9.81 (1H, s), 2.81-2.67 (4H, m), 2.47 (2H, t, J=7 HZ), 1.67-1.53 (2H, m), 1.38-1.21 (4H, m), 0.89 (3H, t, J=7 Hz).

(6c) Benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate

1.50 g (9.60 mmol) of 4-oxononanal obtained in (6b) was dissolved in 45 ml of ethanol-acetic acid (2:1) solution mixture, and 1.60 g (9.60 mmol) of benzyl hydrazinecarboxylate was added thereto, followed by stirring for 1 hour at 80° C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 2.12 g of the title compound as a yellow oil (77% yield).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.36 (5H, bs), 7.21 (1H, ds), 6.63-6.59 (1H, m), 6.07 (1H, t, J=4 Hz), 5.89-5.84 (1H, m), 5.22 (2H, ds), 2.46-2.36 (2H, m), 1.63-1.49 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J=7 Hz).

(6d) 2-Pentyl-1H-pyrrole-1-amine

1.0 g (3.49 mmol) of benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate obtained in (6c) was dissolved in 20 ml of ethanol, and 100 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by stirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 430 mg of the title compound as a yellow oil (yield: 81%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.68 (1H, m), 5.97 (1H, t, J=3 Hz), 5.82-5.77 (1H, m), 4.52 (2H, s), 2.58 (2H, t, J=8 Hz), 1.69-1.57 (2H, m), 1.44-1.31 (4H, m), 0.91 (3H, t, J=7 Hz).

Reference Example 7 2-Hexyl-1H-pyrrol-1-ylamine

Following the procedure described in Reference Example 6, 2-hexylfuran was used as the starting material in place of 2-pentylfuran to give the title compound as a yellow oil (yield: 29%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s), 2.62-2.55 (2H, m), 1.67-1.56 (2H, m), 1.44-1.21 (6H, m), 0.89 (3H, t, J=7 Hz).

Reference Example 8 2-Heptyl-1H-pyrrol-1-ylamine

Following the procedure described in Reference Example 6, 2-heptylfuran was used as the starting material in place of 2-pentylfuran to give the title compound as a pale yellow solid (yield: 59%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s), 2.62-2.55 (2H, m), 1.67-1.53 (2H, m), 1.44-1.21 (8H, m), 0.89 (3H, t, J=7 Hz).

Reference Example 9 2-Octyl-1H-pyrrol-1-ylamine

Following the procedure described in Reference Example 6, 2-octylfuran was used as the starting material in place of 2-pentylfuran to give the title compound as a yellow oil (yield: 11%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.65-6.61 (1H, m), 5.97-5.93 (1H, m), 5.78-5.75 (1H, m), 4.51 (2H, br.s), 2.60-2.55 (2H, m), 1.66-1.54 (2H, m), 1.42-1.21 (10H, m), 0.88 (3H, t, J=7 Hz).

Reference Example 10 2-Cyclopropyl-1H-pyrrol-1-ylamine (10a) 4-Cyclopropyl-4-oxobutanal

230 mg (1.79 mmol) of 1-cyclopropyl-4-hydroxy-1-butanone was dissolved in 7 ml of dichloromethane, and 580 mg (2.69 mmol) of pyridinium chlorochromate was added thereto, followed by stirring for 1 hour at room temperature. To the reaction solution was added diethyl ether, the mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; diethyl ether alone) to give 176 mg of the title compound as a pale yellow oil (yield: 78%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

9.78 (1H, s), 2.91 (2H, t, J=7 Hz), 2.78-2.71 (2H, m), 2.01-1.93 (1H, m), 1.08-1.01 (2H, m), 0.96-0.88 (2H, m).

(10b) 2-Cyclopropyl-1H-pyrrol-1-ylamine

Following the procedures described in Reference Examples (6c) and (6d), 4-cyclopropyl-4-oxobutanal obtained in (10a) was used in place of 4-oxononanal to give the title compound as a pale yellow oil (yield: 45%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.70-6.64 (1H, m), 5.94-5.88 (1H, m), 5.71-5.64 (1H, m), 4.69 (2H, br.s), 1.83-1.72 (1H, m), 0.91-0.83 (2H, m), 0.64-0.57 (2H, m).

Reference Example 11 4-Fluoro-2-heptylphenylamine (11a) 4-Fluoro-2-(hept-1-enyl)-1-nitrobenzene

3.0 g (7.0 mmol) of hexyltriphenylphosphonium bromide was suspended in 30 ml of tetrahydrofuran, and 4.5 ml (7.0 mmol) of n-butyl lithium/hexane solution (1.56 M) was added dropwise thereto at −10° C. After the reaction solution was stirred for 10 minutes at the same temperature, 846 mg (5.0 mmol) of 4-fluoro-2-nitrobenzaldehyde was added, and the reaction solution was further stirred for 1 hour. To the reaction solution was added 1N aqueous potassium hydrogensulfate and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=19:1) to give 917 mg of the title compound as a pale yellow oil (yield: 77%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.09 (1.7H, dd, J=9 Hz, 5 Hz), 7.97 (1H, dd, J=9 Hz, 5 Hz), 7.26-6.99 (5.4H, m), 6.89 (1H, d, J=16 Hz), 6.69 (1.7H, d, J=11 Hz), 6.26 (1H, dt, J=16 Hz, 7 Hz), 5.87 (1.7H, dt, J=12 Hz, 8 Hz), 2.28 (2H, q, J=7 Hz), 2.10 (3.4H, q, J=7 Hz), 1.52-1.23 (16.2H, m), 0.91 (3H, m), 0.86 (5.1H, m).

(11b) 4-Fluoro-2-heptylphenylamine

910 mg (3.8 mmol) of 4-fluoro-2-(hept-1-enyl)-1-nitrobenzene obtained in (11a) was dissolved in 5 ml of ethanol, and 100 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by stirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 730 mg of the title compound as a pale yellow oil (yield: 91%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.80-6.71 (2H, m), 6.61 (1H, dd, J=9 Hz, 5 Hz), 3.47 (2H, brs), 2.45 (2H, t, J=7 Hz), 1.64-1.58 (2H, m), 1.42-1.24 (8H, m), 0.89 (3H, t, J=6 Hz).

Reference Example 12 2-Butyl-4-fluorophenylamine

Following the procedure described in Reference Example 11, propyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a brown oil (yield: 78%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.80-6.69 (2H, m), 6.60 (1H, dd, J=9 Hz, 5 Hz), 3.51 (2H, bs), 2.46 (2H, t, J=8 Hz), 1.63-1.56 (2H, m), 1.45-1.37 (2H, m), 0.96 (3H, t, J=7 Hz).

Reference Example 13 4-Fluoro-2-pentylphenylamine

Following the procedure described in Reference Example 11, butyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a yellow oil (yield: 78%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.80-6.69 (2H, m), 6.60 (1H, dd, J=9 Hz, 5 Hz), 3.50 (2H, bs), 2.45 (2H, t, J=8 Hz), 1.64-1.58 (2H, m), 1.45-1.36 (4H, m), 0.91 (3H, t, J=7 Hz).

Reference Example 14 4-Fluoro-2-hexylphenylamine

Following the procedure described in Reference Example 11, pentyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 63%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.81-6.71 (2H, m), 6.66 (1H, dd, J=9 Hz, 5 Hz), 4.19 (2H, brs), 2.48 (2H, t, J=8 Hz), 1.65-1.57 (2H, m), 1.43-1.25 (6H, m), 0.92-0.85 (3H, m).

Reference Example 15 4-Fluoro-2-octylphenylamine

Following the procedure described in Reference Example 11, heptyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale yellow oil (yield: 65%)

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.80-6.71 (2H, m), 6.61 (1H, dd, J=9 Hz, 5 Hz), 2.45 (2H, t, J=7 Hz), 1.64-1.56 (2H, m), 1.38-1.22 (10H, m), 0.88 (3H, t, J=7 Hz).

Reference Example 16 4-Fluoro-2-nonylphenylamine

Following the procedure described in Reference Example 11, octyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 97%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

6.77 (1H, dd, J=10 Hz, 3 Hz), 6.72 (1H, td, J=8 Hz, 3 Hz), 6.59 (1H, dd, J=9 Hz, 5 Hz), 3.46 (2H, brs), 2.45 (2H, t, J=8 Hz), 1.64-1.56 (2H, m), 1.44-1.21 (12H, m), 0.88 (3H, t, J=7 Hz).

Reference Example 17 2-Decyl-4-fluorophenylamine

Following the procedure described in Reference Example 11, nonyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 67%).

¹H-NMR spectrum (500 MHz, CDCl₃) δ ppm:

6.77 (1H, dd, J=10 Hz, 3 Hz), 6.73 (1H, dd, J=8 Hz, 3 Hz), 6.60 (1H, dd, J=9 Hz, 5 Hz), 3.47 (2H, brs), 2.45 (2H, t, J=8 Hz), 1.64-1.56 (2H, m), 1.43-1.21 (14H, m), 0.88 (3H, t, J=7 Hz).

Reference Example 18 1,4-Di-O-benzoyl-2,3-di-o-trimethylsilyl-D-threitol

17.48 g (52.9 mmol) of 1,4-di-C-benzoyl-D-threitol and 10.8 g (159 mmol) of imidazol were dissolved in 250 ml of dichloromethane, and 12.6 g (116 mmol) of chlorotrimethylsilane was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at room temperature. The reaction solution was directly subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=20:1-5:1) to give 24.59 g of f the title compound as a white powder (yield: 98%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.04 (4H, dd, J=8 Hz, J=1 Hz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m), 4.50 (2H, dd, J=11 Hz, J=4 Hz), 4.48-4.33 (2H, m), 4.13-4.08 (2H, m), 0.14 (18H, s).

Reference Example 19 1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-L-threitol

Following the process described in Reference Example 18, 1,4-di-O-benzoyl-L-threitol was used in place of 1,4-di-o-benzoyl-D-threitol to give the title compound as a white powder (yield: 98%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.04 (4H, dd, J=8 Hz, J=1 Hz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m), 4.50 (2H, dd, J=11 Hz, J=4 Hz), 4.48-4.33 (2H, m), 4.13-4.08 (2H, m), 0.14 (18H, s)

Reference Example 20 Methyl (S)-3,4-bis[(trimethylsilyl)oxy]butyrate

Following the process described in Reference Example 18, methyl (S)-3,4-dihydroxybutyrate was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 62%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.18-4.12 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J=10 Hz, 6 Hz), 3.40 (1H, dd, J=10 Hz, 6 Hz), 2.59 (1H, dd, J=15 Hz, 5 Hz), 2.37 (1H, dd, J=15 Hz, 7 Hz), 0.10 (18H, s).

Reference Example 21 1,4-Anhydro-2,3-di-O-trimethylsilyl-meso-erythritol

Following the process described in Reference Example 1, 1,4-anhydroerythritol was used in place of 1,4-di-o-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 21%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.15-4.10 (2H, m), 3.92-3.85 (2H, m), 3.68-3.62 (2H, m), 0.14 (18H, s).

Reference Example 22 3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane (22a) 3-Ethylhexane-3,4-diol

590 mg (5.0 mmol) of dimethyloxalate was dissolved in 20 ml of tetrahydrofuran, and 22 ml (22 mmol) of 1.0 M ethyl magnesium bromide/tetrahydrofuran solution was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. The reaction solution was made acidic by addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) to give 276 mg of the title compound as an oil (yield: 38%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

3.45-3.41 (1H, m), 1.87 (1H, d, J=6 Hz), 1.75 (1H, s), 1.70-1.31 (6H, m), 1.04 (3H, t, J=7 Hz), 0.89 (3H, t, J=8 Hz), 0.89 (3H, t, J=8 Hz).

(22b) 3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane

270 mg (1.85 mmol) of 3-ethylhexane-3,4-diol obtained in (22a) was dissolved in 5 ml of pyridine, and 597 mg (3.7 mmol) of 1,1,1,3,3,3-hexamethylsilazane and 1.20 g (11 mmol) of chlorotrimethylsilane were added sequentially, followed by stirring for 2 hours at the same temperature and further overnight at room temperature. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 469 mg of the title compound as an oil (yield: 88%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

3.38 (1H, dd, J=9.0 Hz, 3.0 Hz), 1.68-1.33 (6H, m), 0.90 (3H, t, J=6.0 Hz), 0.92-0.90 (6H, m), 0.11-0.08 (18H, m).

Reference Example 23 (R)-1,2-Bis[(trimethylsilyl)oxy]-1,1,2-triphenylethane

Following the process described in Reference Example 18, (R)-1,1,2-triphenyl-1,2-ethanediol was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as a powder (yield: 99%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

7.28-7.18 (15H, m), 5.51 (1H, s), −0.05 (9H, s), −0.16 (9H, s).

Reference Example 24 1,4-Di-O-acetyl-2,3-di-O-trimethylsilyl-D-threitol

Following the process described in Reference Example 18, 1,4-di-O-acetyl-D-threitol was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 96%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

4.20 (2H, dd, J=11 Hz, 4 Hz), 4.01 (2H, dd, J=11 Hz, 7 Hz), 3.88-3.84 (2H, m), 2.06 (6H, s), 0.13 (18H, s).

Reference Example 25 (1R,2R,3R,4R)-4-Benzoyloxy-1-methyl-2,3-bis[(trimethylsilyl)oxy]pentyl benzoate

Following the process described in Reference Example 18, (1R,2S,3S,4R)-4-benzoyloxy-2,3-dihydroxy-1-methylpentyl benzoate was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 86%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.06-8.04 (4H, m), 7.57-7.54 (2H, m), 7.46-7.42 (4H, m), 5.31-5.25 (2H, m), 3.98-3.97 (2H, m), 1.41 (6H, d, J=6 Hz), 0.12 (18H, s).

Reference Example 26 (1R,2R,3R,4R)-4-Benzoyloxy-1-ethyl-2,3-bis[(trimethylsilyl)oxy]hexyl benzoate

Following the process described in Reference Example 18, (1R,2S,3S,4R)-4-benzoyloxy-1-ethyl-2,3-dihydroxyhexyl benzoate was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 82%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47-7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t, J=7 Hz), 0.07 (18H, s).

Reference Example 27 4-Fluoro-2-propylphenylamine

Following the process described in Reference Example 11, ethyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale yellow oil (yield: 17%).

¹H-NMR spectrum (400 MHz, CDCl₃) δ ppm:

6.80-6.59 (3H, m), 3.48 (2H, brs), 2.45 (2H, t, J=7 Hz), 1.70-1.58 (2H, m), 1.01 (3H, t, J=8 Hz).

Test Examples Test Example 1 Suppression Effect Against Endotoxin Stimulated TNF-α Production in Cells (In Vitro)

The suppression rate of the compound according to the present invention against TNF-α production when human monocyte cell line U937 was stimulated by endotoxin, was measured. Specifically, to RPMI1640 medium containing 10% (volume %) of heat-inactivated new born calf serum, was added 12-O-tetradecanoylphorbol 13-acetate so that its final concentration became 30 ng/ml. U937 cells were suspended with the medium and plated to a 96 well culture plate (Sumilon) so that number of cells/volume was 2×10⁴/0.1 ml, and were then cultured for 3 days at 37° C. in a carbon dioxide incubator with 5% CO₂ and 100% humidity. After completion of incubation, the culture supernatant was removed. The compound according to the present invention was added to each of the wells in various concentrations, and lipopolysaccharide (LPS) (E. coli 0111:B4, Sigma) was also added so that its final concentration was 30 ng/ml. After incubating the culture plate in the carbon dioxide incubator again for 4.5 hours, the culture supernatant was collected. By using a 384 half well black plate (Greiner) and HTRF quantitative kit of CIS Bio International, the concentration of TNF-α in the culture supernatant was measured as time-resolved fluorescence with Discovery (Packard). From the measured value in the absence of LPS (X), measured value in the absence of the compound according to the present invention (Y) and measured value in the presence of the compound according to the present invention (Z), the suppression rate of TNF-α production was obtained by the following calculation formula [I]. Suppression rate of TNF-α production (%)={1−(Z−X)/(Y−X)}×100  [I]

In the present test, the compound according to the present invention showed an excellent suppression effect against endotoxin stimulated TNF-α production in cells.

Test Example 2 Suppression Effect Against Elevated TNF-α Concentration in Blood (In Vivo)

The suppression effect of the compound according to the present invention against elevated TNF-α concentration in blood was evaluated. The test for TNF-α concentration elevation in blood was conducted in accordance with the process of Parant et al, which is described in Journal of Leukocyte Biology, Vol. 47, p. 164 (1990).

In the test, 3 to 4 male Sprague Dawley rats (8-9 weeks old) were used for each group.

4 hours before the administration of LPS, muramyl dipeptide dissolved in a physiological saline solution (1 mg/ml) was administered to the tail vein at a rate of 1 ml/kg. 0.5 hours before the administration of LPS, the rats were anaesthetized with pentobarbital (40 mg/kg), and the compound according to the present invention dissolved in 5% dimethyl acetamide/95% polyethylene glycol 400 solution was administered to the right femoral vein at a rate of 1 ml/kg. The control group was administered with 5% dimethyl acetamide/95% polyethylene glycol 400 solution at a rate of 1 ml/kg. LPS dissolved in a physiological saline solution (3 μg/ml) was administered to the left femoral vein at a rate of 1 ml/kg. 2 hours after the administration of LPS, blood was collected using 3.8% (w/v) sodium citrate solution as an anticoagulant, and blood plasma was separated by centrifuge (10,000 g, 5 minutes, 4° C.). TNF-α concentration in the blood plasma was measured using a TNF-α quantitative kit (Bio Source International, Inc.). From the TNF-α concentration in the blood of control group (X) and the TNF-α concentration in the blood of the group administered with the compound according to the present invention (Y), the TNF-α elevation suppression rate was calculated using the following calculation formula [II]. TNF-α elevation suppression rate (%)={1−Y/X}×100  [II]

In the present test, the compound according to the present invention showed excellent suppression effects against elevated TNF-α concentration in blood. 

1. A compound represented by the general formula (I):

{wherein X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, or X and Y together represent a substituent of ring B, or X and Y each represents a hydrogen atom; (1) in the case where X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A: ring A represents a 3- to 7-membered heterocyclyl ring (in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkanoyl group which may be substituted with one or more groups selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂, the heterocyclyl ring may include an unsaturated bond, may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆ alkyl group, a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α, a C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α, and a C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group α) or a 3- to 7-membered cycloalkyl ring (the cycloalkyl ring may include an unsaturated bond, may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of Substituent group α, a cyclopropyl C₁-C₆ alkyl group, a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α, a C₂-C₆ alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α, and a C₂-C₆ alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group α); (2) in the case where X and Y together represent a substituent of ring B: X and Y represent an oxo group or a thioxo group; 1 and m, independently from each other, represent an integer of 0 to 3, and 1+m is 1 to 3; R¹ represents an aliphatic hydrocarbon group which may be substituted with one or more groups selected from Substituent group β and Substituent group γ (wherein the aliphatic hydrocarbon group represents a C₁-C₂₀ alkyl group, C₃-C₁₀cycloalkyl group, C₄-C₁₂ cycloalkylalkyl group, C₃-C₆ alkenyl group or C₃-C₆ alkynyl group), a phenyl group which may be substituted with one or more groups selected from Substituent group δ, a group having the formula OR⁴ (R⁴ represents a hydrogen atom or an aliphatic hydrocarbon group which may be substituted with one or more groups selected from Substituent group β and Substituent group γ, the aliphatic hydrocarbon group has the same meaning as defined above) or a halogen atom; n represents an integer of 0 to 3; R² represents a hydrogen atom, a C₁-C₆ alkyl group which may be substituted with one or more groups selected from Substituent group β, a C₂-C₆ alkenyl group which may be substituted with one or more groups selected from Substituent group β, or a C₂-C₆ alkynyl group which may be substituted with one or more groups selected from Substituent group β; R³ represents a phenyl group which may be substituted with one or more groups selected from Substituent group ε, or a 5- or 6-membered heteroaryl group which may be substituted with one or more groups selected from Substituent group ε (the heteroaryl group includes 1 to 3 hetero atoms selected from a nitrogen atom, oxygen atom and sulfur atom); R⁵ represents a hydrogen atom, a C₁-C₆ alkyl group which may be substituted with one or more groups selected from Substituent group β, a C₂-C₆ alkenyl group which may be substituted with one or more groups selected from Substituent group β, or a C₂-C₆ alkynyl group which may be substituted with one or more groups selected from Substituent group β; provided that in the case where R³ is a phenyl group which may be substituted with one or more groups selected from Substituent group ε, X and Y represent the aforementioned (1) or (2); Substituent group α represents a hydroxy group, halogen atom, C₁-C₆ alkoxy group, halogeno C₁-C₆ alkoxy group, carboxy group, C₁-C₆ alkoxy-carbonyl group; carbamoyl group which may be substituted with one or more groups selected from a C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆ alkanoyl group or C₂-C₆ alkenyl-carbonyl group; and a group having the formula NR⁶R⁷, and R⁶ and R⁷, independently from each other, represent a hydrogen atom, C₁-C₆ alkyl group, C₂-C₆ alkenyl group, C₂-C₆ alkynyl group, C₁-C₆ alkanoyl group or C₂-C₆ alkenyl-carbonyl group, or together with the nitrogen atom to which they are bound form a heterocyclyl group; Substituent group β represents an oxo group, hydroxy group, cyclopropyl group, C₁-C₆ alkoxy group, C₁-C₆ alkylthio group, nitro group, halogen atom, cyano group, carboxy group, C₁-C₁₀ alkoxy-carbonyl group, C₁-C₆ alkanoyl group, C₂-C₄ alkenyl-carbonyl group, C₂-C₆ alkanoyloxy group, C₂-C₄ alkenyl-carbonyloxy group; carbamoyl group which may be substituted with one or more groups selected from a C₁-C₄ alkyl group, phenyl group, C₁-C₇ acyl group and C₁-C₄ alkoxy-phenyl group; thiocarbamoyl group which may be substituted with a C₁-C₄ alkyl group or phenyl group; carbamoyloxy group which may be substituted with a C₁-C₄ alkyl group or phenyl group; C₁-C₆ alkanoylamino group, C₁-C₁₀ alkoxy-carboxamide group, C₁-C₁₀ alkoxy-carbonyloxy group, and ureido group which may be substituted with a C₁-C₄ alkyl group or phenyl group; Substituent group γ represents a heterocyclic group, C₃-C₁₀ cycloalkyloxy group, C₆-C₁₀ aryloxy group, C₇-C₁₉ aralkyloxy group, heterocyclyloxy group, C₃-C₁₀ cycloalkylthio group, C₆-C₁₀ arylthio group, C₇-C₁₉ aralkylthio group, heterocyclylthio group, heterocyclylsulfinyl group, heterocyclylsulfonyl group, C₃-C₆ cycloalkyloxy-carbonyl group, C₆-C₁₀ aryloxy-carbonyl group, C₇-C₁₉ aralkyloxy-carbonyl group, heterocyclyloxycarbonyl group, C₆-C₁₀aryl-carbonyl group, C₆-C₁₀ aryl-carbonyloxy group, C₆-C₁₀ aryl-carbonylamino group, C₆-C₁₀ aryloxy-carboxamide group, C₇-C₁₉ aralkyloxy-carboxamide group, C₆-C₁₀ aryloxy-carbonyloxy group, C₇-C₁₉ aralkyloxy-carbonyloxy group, C₃-C₁₀ cycloalkyloxy-carbonyloxy group and C₆-C₁₀ aryl group which may be substituted with one or more groups selected from Substituent group β; Substituent group δ represents a hydroxy group, nitro group, cyano group, halogen atom, C₁-C₆ alkyl group, halogeno C₁-C₆ alkyl group, C₁-C₆ alkoxy group, halogeno C₁-C₆ alkoxy group, carboxy group, C₁-C₆ alkanoyl group, C₁-C₆ alkoxy-carbonyl group, C₁-C₆ alkanoylamino group, C₁-C₆ alkylthio group, carbamoyl group, C₁-C₆ alkyl-carbamoyl group, C₁-C₆ alkoxy-carbonyl C₁-C₆ alkyl-carbamoyl group, 1,3-diacylguanidino C₁-C₆ alkyl group, a group having the formula NR⁶R⁷ (R⁶ and R⁷ are the same as R⁶ and R⁷ of Substituent group α), C₃-C₆ cycloalkyl group, C₆-C₁₀ aryl group and 5-membered heteroaryl group; and Substituent group ε represents a hydroxy group, nitro group, cyano group, halogen atom, C₁-C₁₄ alkyl group, cyclopropyl C₁-C₁₄ alkyl group, halogeno C₁-C₁₄ alkyl group, C₁-C₁₄ alkoxy group, halogeno C₁-C₁₄ alkoxy group, carboxy group, C₁-C₁₄ alkanoyl group, C₁-C₁₄ alkoxy-carbonyl group, C₁-C₁₄ alkanoylamino group, C₁-C₁₄ alkylthio group, carbamoyl group, C₁-C₁₄ alkyl-carbamoyl group, C₁-C₁₄ alkoxy-carbonyl C₁-C₁₄ alkyl-carbamoyl group, 1,3-diacylguanidino C₁-C₁₄ alkyl group, group having the formula NR⁶R⁷ (R⁶ and R⁷ are the same as R⁶ and R⁷ of Substituent group α), C₃-C₆ cycloalkyl group, C₆-C₁₀ aryl group and 5-membered heteroaryl group} or a pharmacologically acceptable salt thereof.
 2. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein 1 is 0 and m is an integer of 1 to
 3. 3. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein 1 is 0 and m is
 2. 4. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring (in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkanoyl group which may be substituted with one or more groups selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO₂, the heterocyclyl ring may form a fused ring or Spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- to 6-membered cycloalkyl ring, and ring A, including the fused ring or Spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C₁-C₆ alkyl group and a C₁-C₆ alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α) or a 3- to 7-membered saturated cycloalkyl ring (the 3- to 7-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxy group, hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group).
 5. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring (in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, an oxygen atom, sulfur atom, a group having the formula SO and a group having the formula SO₂, the heterocyclyl ring may form a fused ring or Spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered cycloalkyl ring, and ring A, including the fused ring or Spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α and a C₁-C₆ alkyl group which may be substituted with 1 to 4 groups selected from Substituent group α) or a 3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group).
 6. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring (the 3- to 7-membered heterocyclyl ring is oxirane, oxolane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and ring A, including the fused ring and spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α (Substituent group α represents a hydroxy group and a group having the formula NR⁶R⁷, and R6 and R⁷, independently from each other, represent a hydrogen atom or C₁-C₆ alkanoyl group), a methyl group, an ethyl group and a C₁-C₆ alkyl group which is substituted with 1 to 4 hydroxy groups), or a cyclopropyl or cyclopentyl ring (the cyclopropyl or cyclopentyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group).
 7. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 6-membered heterocyclyl ring {the heterocyclyl ring is oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, or 1,3-oxathiane, these heterocyclyl rings may form a fused ring or Spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3-dioxane) or cyclohexyl ring, and ring A, including the fused ring or spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of Substituent group α (Substituent group α represents a hydroxy group and a group having the formula NR⁶R⁷ (R⁶ and R⁷, independently from each other, represent a hydrogen atom or acetyl group), a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group}.
 8. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein n is 0 or 1, and R¹ is a hydroxy group, halogen atom, C₁-C₆ alkyl group or C₁-C₆ alkoxy group.
 9. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein n is 0 or 1, and R¹ is a fluorine atom or methyl group.
 10. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein n is
 0. 11. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R² is a C₁-C₆ alkyl group.
 12. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R² is a C₁-C₄ alkyl group.
 13. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R² is an ethyl group.
 14. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R³ is a phenyl group which may be substituted with one or more groups selected from Substituent group ε, or a pyrrolyl group which may be substituted with one or more groups selected from Substituent group ε, and Substituent group ε is a halogen atom, C₁-C₁₄ alkyl group and halogeno C₁-C₁₄ alkyl group.
 15. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R³ is a phenyl group which may be substituted with one or more groups selected from Substituent group ε, or a pyrrolyl group which may be substituted with one or more groups selected from Substituent group ε, and Substituent group ε is a fluorine atom, chlorine atom, bromine atom, C₃-C₈ alkyl group and halogeno C₄-C₈ alkyl group.
 16. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R³ is a phenyl group which may be substituted with one or more groups selected from Substituent group ε, and Substituent group ε is a fluorine atom, chlorine atom and C₃-C₈ alkyl group.
 17. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R⁵ is a hydrogen atom or C₁-C₆ alkyl group.
 18. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R⁵ is a hydrogen atom or methyl group.
 19. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R⁵ is a hydrogen atom.
 20. The compounds of the following group selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chloropheny)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloropheny)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluoropheny)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluoropheny)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3-trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, ethyl 3-acetylamino-9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-butyl-4-fluoropheny)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(hydroxymethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, and ethyl 8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 21. A pharmaceutical composition or pharmacologically acceptable salt thereof comprising any of the compounds according to claim 1, and a pharmaceutically acceptable excipient.
 22. A method for suppressing intracellular signal transduction or cell activation induced by, endotoxin comprising the administration of an effective amount of the pharmaceutical composition or pharmaceutically acceptable salt thereof according to claim
 21. 23. A method for suppressing the generation of inflammatory mediators due to intracellular signal transduction or cell activation induced by endotoxin comprising the administration of an effective amount of the pharmaceutical composition or pharmaceutically acceptable salt thereof according to claim
 21. 24. A method for treatment of sepsis comprising the administration of an effective amount of the pharmaceutical composition or pharmaceutically acceptable salt thereof according to claim
 21. 25. The compounds of the following group selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, and ethyl 2,3-bis(1,2-dihydroxyethyl)-8[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 26. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl) -1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 27. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 28. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl) -1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 29. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 30. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl) -1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 31. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl) -1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
 32. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl) -1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 33. The following compound selected from claim 1 or pharmacologically acceptable salt thereof: ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 34. A pharmaceutically acceptable salt of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 35. A potassium salt of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 36. A pharmaceutical composition comprising the compound according to claim 34, and a pharmaceutically acceptable excipient.
 37. A method for treating sepsis comprising administering a pharmaceutical composition comprising the compound according to claim 34, and a pharmaceutically acceptable excipient.
 38. A pharmaceutical composition comprising the compound according to claim 35, and a pharmaceutically acceptable excipient.
 39. A method of treating sepsis comprising administering a pharmaceutical composition comprising the compound according to claim 35, and a pharmaceutically acceptable excipient.
 40. A pharmaceutically acceptable salt of ethyl (2R,3R,8R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4dioxaspiro[4.5]dec-6-ene-7-carboxylate.
 41. Potassium (2-chloro-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl] sulfonyl}azanide.
 42. A pharmaceutical composition comprising the compound according to claim 40, and a pharmaceutically acceptable excipient.
 43. A method for treating sepsis comprising administering a pharmaceutical composition comprising the compound according to claim 40, and a pharmaceutically acceptable excipient.
 44. A pharmaceutical composition comprising the compound according to claim 41, and a pharmaceutically acceptable excipient.
 45. A method for treating sepsis comprising administering a pharmaceutical composition comprising the compound according to claim 41, and a pharmaceutically acceptable excipient. 